Stents combined with paclitaxel derivatives

ABSTRACT

Stents are used in combination with a paclitaxel derivative in order to inhibit scarring that may otherwise occur when the implant is placed within an animal. Suitable implants include vascular stents, esophageal stents, tracheal or bronchial stents, gastrointestinal stents, genital-urinary stents, nasal and sinus stents, and ENT stents.

CROSS-REFERENCE TO RELATED APPLICATION

This application claims the benefit under 35 U.S.C. § 119(e) of U.S.Provisional Patent Application No. 60/653,844, filed Feb. 17, 2005,which application is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates generally to pharmaceutical compositionsthat include paclitaxel derivatives and methods for preparing and usingstent devices to make them resistant to overgrowth by inflammatory andfibrous scar tissue.

2. Description of the Related Art

The clinical function of numerous medical implants and devices isdependent upon the device being able to effectively maintain ananatomical, or surgically created, space or passageway. Unfortunately,many devices implanted in the body are subject to a “foreign body”response from the surrounding host tissues. In particular, injury totubular anatomical structures (such as blood vessels, thegastrointestinal tract, the male and female reproductive tract, theurinary tract, sinuses, spinal nerve root canals, lacrimal ducts,Eustachian tubes, the auditory canal, and the respiratory tract) fromsurgery and/or injury created by the implantation of medical devices canlead to a well known clinical problem called “stenosis” (or narrowing).Stenosis occurs in response to trauma to the epithelial lining or theentire body tube during the procedure, including virtually anymanipulation which attempts to relieve obstruction of the passageway,and is a major factor limiting the effectiveness of invasive treatmentsfor a variety of diseases to be described later.

Stenosis (or “restenosis” if the problem recurs after an initiallysuccessful attempt to open a blocked passageway) is a form of responseto injury leading to wall thickening, narrowing of the lumen, and lossof function in the tissue supplied by the particular passageway.Physical injury during an interventional procedure results in damage toepithelial lining of the tube and the smooth muscle cells (SMCs) thatmake up the wall. The damaged cells, particularly SMCs, releasecytokines, which recruit inflammatory cells such as macrophages,lymphocytes and neutrophils (i.e., which are some of the known whiteblood cells) into the area. The white blood cells in turn release avariety of additional cytokines, growth factors, and tissue degradingenzymes that influence the behavior of the constituent cells of the wall(primarily epithelial cells and SMCs). Stimulation of the SMCs inducesthem to migrate into the inner aspect of the body passageway (oftencalled the “intima”), proliferate and secrete an extracellarmatrix—effectively filling all or parts of the lumen with reactive,fibrous scar tissue. Collectively, this creates a thickening of theintimal layer (known in some tissues as “neointimal hyperplasia” thatnarrows the lumen of the passageway and can be significant enough toobstruct its lumen.

BRIEF SUMMARY OF THE INVENTION

Briefly stated, in one aspect, the present invention provides medicaldevices (e.g., stents) that are coated or otherwise contain paclitaxelderivatives or compositions comprising paclitaxel derivatives, methodsfor making such devices, methods for inhibiting fibrosis comprisingplacing medical devices that are coated with, or otherwise contain,paclitaxel derivatives or compositions comprising paclitaxelderivatives, and methods for inhibiting fibrosis comprising separatelyplacing a medical device and applying at least one of (i) a paclitaxelderivative and (ii) a composition that comprises a paclitaxel derivativeinto an animal. Paclitaxel derivatives or compositions comprisingpaclitaxel derivatives are delivered in therapeutic levels over a periodsufficient to allow normal healing to occur at or near the site where amedical device is implanted. For example, within one aspect of theinvention, paclitaxel derivate-coated or paclitaxel derivate-impregnatedmedical devices are provided that reduce fibrosis in the tissuesurrounding the devices or inhibit scar development on the devicesurface.

The repair of tissues following a mechanical or surgical interventioninvolves two distinct processes: (1) regeneration (the replacement ofinjured cells by cells of the same type) and (2) fibrosis (thereplacement of injured cells by connective tissue). There are fourgeneral components to the process of fibrosis (or scarring) including:formation of new blood vessels (angiogenesis), migration andproliferation of connective tissue cells (such as fibroblasts or smoothmuscle cells), deposition of extracellular matrix (ECM), and remodeling(maturation and organization of the fibrous tissue). Within oneembodiment of the invention, a device is adapted to release a paclitaxelderivative that inhibits fibrosis or regeneration through one or more ofthe mechanisms sited herein.

In one aspect, the present invention provide a device, comprising astent and a paclitaxel derivative or a composition comprising apaclitaxel derivative, wherein the paclitaxel derivative inhibitsscarring between the device and a host into which the device isimplanted.

In certain embodiments, the paclitaxel derivative may be 9-deoxotaxol,7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol, 9-dihydrotaxolcompound, 2′-O-ethoxyethyl-7-O-trietylsilyl-9-dihydrotaxol,2′-O-ethoxyethyl-9-dihydrotaxol, 10-deacetyl-9-dihydrotaxol,9-dihydrotaxol-7,9-isopropylidene ketal, 9-dihydrotaxol-7,9-propylideneacetal, 9-dihydrotaxol-7,9-benzylidene acetal,9-dihydrotaxol-7,9-(3,4-dihydroxy)butylidene acetal,9-dihydrotaxol-7,9-thionocarbonate, 9-dihydrotaxol-7-O-allyl ether,9-dihydrotaxol-7-O-(2,3-dihydroxypropyl) ether, 9-dihydrotaxol7-O-(2-dimethylaminoethyl) ether, 9-dihydrotaxol 7-O-(2-hydroxyethyl)ether, 9-dihydrotaxol 7-O-(2-acetoxyethyl) ether,N-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol,10-deacetyl-N-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-t-butylacetyl-9-dihydrotaxol,N-debenzoyl-N-isobutoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-adamantoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-isopropoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-benzyloxycarbonyl-9-dihydrotaxol,N-debenzoyl-9-dihydrotaxol, N-debenzoyl-N-pivaloyl-9-dihydrotaxol,N-debenzoyl-N-acetyl-9-dihydrotaxol,N-debenzoyl-N-t-butylcarbamyl-9-dihydrotaxol,9-dihydro-13-acetylbaccatin III, 2′-O-(1-ethyoxyethyl)-9-dihydrotaxol,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester,4,9,12(tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-1-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylphosphate,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-1-undecahydro-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3.4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylphosphate,4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,b-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cycionona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, 1,3-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methyihydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester,β-benzoylamino-α-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yi)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-terttert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17otetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(1-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(2-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(pyridyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-yl ester,β-tert-benzoylamino-α-hydroxy-γ-(thienyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(furyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxyo1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(oxazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(imidazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(pyrazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(pyridazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.

In certain embodiments, the paclitaxel derivative inhibits adhesionbetween the device and a host into which the device is implanted. Incertain embodiments, the device delivers the paclitaxel derivativelocally to tissue proximate to the device.

In certain embodiments, the device further comprises a coating, whereinthe coating comprises the paclitaxel derivative. In certain embodiments,the coating is disposed on a surface of the device. In certainembodiments, the coating directly contacts the device. In certain otherdevices, the coating indirectly contacts the device. In certainembodiments, the coating partially covers the device. In certain otherembodiments, the coating completely covers the device. In certainembodiments, the coating is a uniform coating. In certain otherembodiments, the coating is a non-uniform coating. In certainembodiments, the coating is a discontinuous coating. In certain otherembodiments, the coating is a patterned coating. In certain embodiments,the coating has a thickness of 100 μm or less. In certain otherembodiments, the coating has a thickness of 10 μm or less. In certainembodiments, the coating adheres to the surface of the device upondeployment of the device. In certain embodiments, the coating is stableat room temperature for a period of 1 year. In certain embodiments, thepaclitaxel derivative is present in the coating in an amount rangingbetween about 0.0001% to about 1% by weight. In certain otherembodiments, the paclitaxel derivative is present in the coating in anamount ranging between about 1% to about 10% by weight. In yet otherembodiments, the paclitaxel derivative is present in the coating in anamount ranging between about 10% to about 25% by weight. In certainother embodiments, the paclitaxel derivative is present in the coatingin an amount ranging between about 25% to about 70% by weight. Incertain embodiments, the coating further comprises a polymer.

In certain embodiments, the device further comprises a first coatinghaving a first composition and the second coating having a secondcomposition. In certain embodiments, the device further comprises afirst coating having a first composition and the second coating having asecond composition, wherein the first composition and the secondcomposition are different.

In certain embodiments, the device further comprises a lubriciouscoating.

In certain embodiments, the device comprises a polymer or polymericcarrier. In certain embodiments, the polymeric carrier comprises acopolymer (e.g., a block copolymer or a random copolymer). In certainembodiments, the polymeric carrier comprises a biodegradable polymer. Incertain other embodiments, the polymeric carrier comprises anon-biodegradable polymer. In certain embodiments, the polymeric carriercomprises a hydrophilic polymer. In certain other embodiments, thepolymeric carrier comprises a hydrophobic polymer. In certainembodiments, the polymeric carrier comprises a polymer havinghydrophilic domains. In certain embodiments, the polymeric carriercomprises a polymer having hydrophobic domains. In certain embodiments,the polymeric carrier comprises a non-conductive polymer. In certainembodiments, the polymeric carrier comprises an elastomer. In certainembodiments, the polymeric carrier comprises a hydrogel. In certainembodiments, the polymeric carrier may comprise a silicone polymer, ahydrocarbon polymer, a styrene-derived polymer, a butadiene polymer, amacromer, a poly(ethylene glycol) polymer, or an amorphous polymer.

In certain embodiments, the paclitaxel derivative is located withinpores or holes of the device. In certain other embodiments, thepaclitaxel derivative is located within a channel, lumen, or divet ofthe device.

In certain embodiments, the device further comprises a secondpharmaceutically active agent, including an anti-inflammatory agent, anagent that inhibits infection (e.g., an anthracycline, doxorubicin,mitoxantrone, a fluoropyrimidine, 5-fluorouracil (5-FU), a folic acidantagonist, methotrexate, a podophylotoxin, etoposide, a camptothecin, ahydroxyurea, a platinum complex, and cisplatin, an anti-thromboticagent, a visualization agent (e.g., a radiopaque material comprising ametal, a halogenated compound, or a barium containing compound, aradiopaque material comprising barium, tantalum, or technetium, a MRIresponsive material, a visualization agent comprising a gadoliniumchelate, a visualization agent comprising iron, magnesium, manganese,copper, or chromium, a visualization agent comprising an iron oxidecompound, a visualization agent comprising a dye, pigment, or colorant),or an echogenic material (e.g., in the form of a coating).

In certain embodiments, the device is sterile.

In certain embodiments, the paclitaxel derivative is released intotissue in the vicinity of the device after deployment of the device. Incertain embodiments, the tissue may be connective tissue, muscle tissue,nerve tissue, or epithelium tissue.

In certain embodiments, the paclitaxel derivative is released ineffective concentrations from the device over a period ranging from thetime of deployment of the device to about 1 year, over a period rangingfrom about 1 month to 6 months, or over a period ranging from about 1-90days.

In certain embodiments, the paclitaxel derivative is released ineffective concentrations from the device at a constant rate. In certainother embodiments, the paclitaxel derivative is released in effectiveconcentrations from the device at an increasing rate. In yet otherembodiments, the paclitaxel derivative is released in effectiveconcentrations from the device at a decreasing rate.

Within various embodiments of the invention, the device is furthercoated with a composition or compound, which delays the onset ofactivity of the paclitaxel derivative for a period of time afterimplantation. Representative examples of such agents include heparin,PLGA/MePEG, PLA, and polyethylene glycol. Within further embodiments,the fibrosis-inhibiting implant or device is activated before, during,or after deployment (e.g., an inactive agent on the device is firstactivated to one that reduces or inhibits an in vivo fibrotic reaction).

In certain embodiments, the paclitaxel derivative is released ineffective concentrations from the composition comprising the paclitaxelderivative by diffusion over a period ranging from the time ofdeployment of the device to about 90 days. In certain other embodiments,the paclitaxel derivative is released in effective concentrations fromthe composition comprising the paclitaxel derivative by erosion of thecomposition over a period ranging from the time of deployment of thedevice to about 90 days.

In certain embodiments, the device may comprise about 0.01 μg to about10 μg, about 10 μg to about 10 mg, about 10 mg to about 250 mg, about250 mg to about 1000 mg, or about 1000 mg to about 2500 mg of thepaclitaxel derivative.

In certain embodiments, a surface of the device comprises less than 0.01μg, about 0.01 μg to about 1 μg, about 1 μg to about 10 μg, about 10 μgto about 250 μg, about 250 μg to about 1000 μg, or about 1000 μg toabout 2500 μg of the paclitaxel derivative per mm² of device surface towhich the paclitaxel derivative is applied.

In certain embodiments, the stent may be a vascular stent, a coronarystent, a peripheral stent, a covered stent, a gastrointestinal stent, anesophageal stent, a biliary stent, a colonic stent, a tracheal orbronchial stent, a genital-urinary stent, a nasal or sinus stent, or anENT stent.

The present invention provides combinations of each of medical devices(e.g., various types of stents) disclosed herein with each of paclitaxelderivatives disclosed herein. In addition, for each combination, thepaclitaxel derivative may be present in a composition along with one ofpolymers disclosed herein.

Within yet other aspects of the present invention, methods are providedfor manufacturing a medical device, comprising the step of coating(e.g., spraying, dipping, wrapping, or administering drug through) astent. Additionally, the implant or medical device can be constructed sothat the stent itself is comprised of materials that comprise apaclitaxol derivative. A wide variety of stent devices may be utilizedwithin the context of the present invention, depending on the site andnature of treatment desired.

Also provided by the present invention are methods for treating patientsundergoing surgical, endoscopic or minimally invasive therapies where amedical device or implant is placed as part of the procedure. Asutilized herein, it should be understood that “inhibits fibrosis orstenosis” refers to a statistically significant decrease in the amountof scar tissue in or around the device or an improvement in the luminalarea of the device/implant, which may or may not result in a permanentprohibition of any complications or failures of the device/implant.

In one aspect, the present invention provides methods for inhibitingfibrosis comprising placing a medical device that is coated or otherwisecontains a paclitaxel derivative or a composition comprising apaclitaxel derivative. Paclitaxel derivatives and compositionscomprising paclitaxel derivatives contained in medical devices reducethe foreign body response to implantation of the medical devices andlimit the growth of reactive tissue on the surface of, or around in thetissue surrounding the devices, such that performance is enhanced. Inmany instances, the devices are used to maintain body lumens orpassageways such as blood vessels, the gastrointestinal tract, the maleand female reproductive tract, the urinary tract, bony foramena (e.g.,sinuses, spinal nerve root canals, lacrimal ducts, Eustachian tubes, theauditory canal), and the respiratory tract, where obstruction of thedevice by scar tissue in the post-procedural period leads to the adverseclinical sequela or failure of the intervention. Medical devices coatedwith, or otherwise containing, paclitaxel derivatives designed toprevent scar tissue overgrowth and preserve patency can offersignificant clinical advantages over uncoated devices.

In another aspect, the present invention is directed to methods forinhibiting fibrosis wherein a medical device and at least one of (i) apaclitaxel derivative and (ii) a composition that comprises a paclitaxelderivative are separately placed or applied into an animal, and thepaclitaxel derivative inhibits fibrosis that can otherwise occur at ornear the tissue where the medical device is placed. The medical devicemay be placed .into an animal prior to, simultaneously, or subsequentto, the application of a paclitaxel derivative (or a compositioncomprising a paclitaxel derivative) to the site where the medical devicehas been, is being, or is to be, inserted.

These and other aspects of the present invention will become evidentupon reference to the following detailed description and attacheddrawings. In addition, various references are set forth herein whichdescribe in more detail certain procedures and/or compositions (e.g.,polymers), and are therefore incorporated by reference in the entirety.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a picture that shows an uninjured carotid artery from a ratballoon injury model.

FIG. 2 is a picture that shows an injured carotid artery from a ratballoon injury model.

FIG. 3 is a picture that shows a paclitaxel/mesh treated carotid arteryin a rat balloon injury model (345 μg paclitaxel in a 50:50 PLG coatingon a 10:90 PLG mesh).

FIG. 4A schematically depicts the transcriptional regulation of matrixmetalloproteinases.

FIG. 4B is a blot which demonstrates that IL-1 stimulates AP-1transcriptional activity.

FIG. 4C is a graph that shows that IL-1 induced binding activitydecreased in lysates from chondrocytes which were pretreated withpaclitaxel.

FIG. 4D is a blot which shows that IL-1 induction increases collagenaseand stromelysin in RNA levels in chondrocytes, and that this inductioncan be inhibited by pretreatment with paclitaxel.

FIGS. 5A-H are blots that show the effect of various anti-microtubuleagents in inhibiting collagenase expression.

FIG. 6 is a graph showing the results of a screening assay for assessingthe effect of paclitaxel on smooth muscle cell migration (paclitaxelIC₅₀=0.76 nM).

FIG. 7 is graph showing the results of a screening assay for assessingthe effect of paclitaxel on proliferation of smooth muscle cells.

FIG. 8 is graph showing the results of a screening assay for assessingthe effect of paclitaxel on cell proliferation of human fibroblasts.

FIG. 9 is graph showing the results of a screening assay for assessingthe effect of paclitaxel (IC₅₀=134 nM) for proliferation of the murineRAW 264.7 macrophage cell line.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

Prior to setting forth the invention, it may be helpful to anunderstanding thereof to first set forth definitions of certain termsthat are used herein.

“Fibrosis,” “Scarring,” or “Fibrotic Response” refers to the formationof fibrous tissue in response to injury or medical intervention.Therapeutic agents which inhibit fibrosis or scarring (e.g., paclitaxelderivatives) are those agents inhibit fibrosis through one or moremechanisms including: inhibiting angiogenesis, inhibiting migration orproliferation of connective tissue cells (such as fibroblasts, smoothmuscle cells, vascular smooth muscle cells), reducing ECM production,and/or inhibiting tissue remodeling.

“Host,” “Person,” “Subject,” “Patient” and the like are usedsynonymously to refer to the living being into which a device of thepresent invention is implanted.

“Implanted” refers to having completely or partially placed a devicewithin a host. A device is partially implanted when some of the devicereaches, or extends to the outside of, a host.

“Inhibit fibrosis,” “reduce fibrosis” and the like are used synonymouslyto refer to the action of agents or compositions which result in astatistically significant decrease in the formation of fibrous tissuethat can be expected to occur in the absence of the agent orcomposition.

“Medical device,” “implant,” “medical device or implant,”“Implant/device,” and the like are used synonymously to refer to anyobject that is designed to be placed partially or wholly within apatient's body for one or more therapeutic or prophylactic purposes suchas for restoring physiological function, alleviating symptoms associatedwith disease, delivering therapeutic agents, and/or repairing orreplacing or augmenting etc. damaged or diseased organs and tissues.While normally composed of biologically compatible synthetic materials(e.g., medical-grade stainless steel, titanium and other metals;polymers such as polyurethane, silicon, PLA, PLGA and other materials)that are exogenous, some medical devices and implants include materialsderived from animals (e.g., “xenografts” such as whole animal organs;animal tissues such as heart valves; naturally occurring orchemically-modified molecules such as collagen, hyaluronic acid,proteins, carbohydrates and others), human donors (e.g., “allografts”such as whole organs; tissues such as bone grafts, skin grafts andothers), or from the patients themselves (e.g., “autografts” such assaphenous vein grafts, skin grafts, tendon/ligament/muscle transplants).Medical devices of particular utility in the present invention include,but are not restricted to, vascular stents, gastrointestinal stents,tracheal/bronchial stents, genital-urinary stents, and ENT stents.

“Release of an agent” refers to a statistically significant presence ofthe agent, or a subcomponent thereof, which has disassociated from theimplant/device.

“Biodegradable” refers to materials for which the degradation process isat least partially mediated by, and/or performed in, a biologicalsystem. “Degradation” refers to a chain scission process by which apolymer chain is cleaved into oligomers and monomers. Chain scission mayoccur through various mechanisms, including, for example, by chemicalreaction (e.g., hydrolysis) or by a thermal or photolytic process.Polymer degradation may be characterized, for example, using gelpermeation chromatography (GPC), which monitors the polymer molecularmass changes during erosion and drug release. “Biodegradable” alsorefers to materials may be degraded by an erosion process mediated by,and/or performed in, a biological system. “Erosion” refers to a processin which material is lost from the bulk. In the case of a polymericsystem, the material may be a monomer, an oligomer, a part of a polymerbackbone, or a part of the polymer bulk. Erosion includes (i) surfaceerosion, in which erosion affects only the surface and not the innerparts of a matrix; and (ii) bulk erosion, in which the entire system israpidly hydrated and polymer chains are cleaved throughout the matrix.Depending on the type of polymer, erosion generally occurs by one ofthree basic mechanisms (see, e.g., Heller, J., CRC Critical Review inTherapeutic Drug Carrier Systems (1984), 1(1), 39-90); Siepmann, J. etal., Adv. Drug Del. Rev. (2001), 48, 229-247): (1) water-solublepolymers that have been insolubilized by covalent cross-links and thatsolubilize as the cross-links or the backbone undergo a hydrolyticcleavage; (2) polymers that are initially water insoluble aresolubilized by hydrolysis, ionization, or pronation of a pendant group;and (3) hydrophobic polymers are converted to small water-solublemolecules by backbone cleavage. Techniques for characterizing erosioninclude thermal analysis (e.g., DSC), X-ray diffraction, scanningelectron microscopy (SEM), electron paramagnetic resonance spectroscopy(EPR), NMR imaging, and recording mass loss during an erosionexperiment. For microspheres, photon correlation spectroscopy (PCS) andother particles size measurement techniques may be applied to monitorthe size evolution of erodible devices versus time.

“Body passageway” as used herein refers to any of number of passageways,tubes, pipes, tracts, canals, sinuses or conduits which have an innerlumen and allow the flow of materials within the body. Representativeexamples of body passageways include arteries and veins, lacrimal ducts,the trachea, bronchi, bronchiole, nasal passages (including the sinuses)and other airways, eustachian tubes, the external auditory canal, theesophagus, the stomach, the duodenum, the small intestine, the largeintestine, biliary tracts, the ureter, the bladder, the urethra, thefallopian tubes, uterus, vagina and other passageways of the femalereproductive tract, the vas deferens and other passageways of the malereproductive tract.

Any concentration ranges, percentage range, or ratio range recitedherein are to be understood to include concentrations, percentages orratios of any integer within that range and fractions thereof, such asone tenth and one hundredth of an integer, unless otherwise indicated.Also, any number range recited herein relating to any physical feature,such as polymer subunits, size or thickness, are to be understood toinclude any integer within the recited range, unless otherwiseindicated. It should be understood that the terms “a” and “an” as usedabove and elsewhere herein refer to “one or more” of the enumeratedcomponents. For example, “a” polymer refers to both one polymer and amixture comprising two or more polymers. As used herein, the term“about” means ±15%.

As discussed above, the present invention provides compositions, methodsand devices, which greatly increase the ability to inhibit the formationof reactive scar tissue on, or around, the surface of the device.Described in more detail below are methods for constructing medicalimplants, compositions and methods for generating medical implants whichinhibit fibrosis, and methods for utilizing such medical implants.

A. Stents

In one aspect, the present invention provides medical implants thatcomprise a stent device and a paclitaxel derivative or a compositioncomprising a paclitaxel derivative, wherein the paclitaxel derivativeinhibits scarring between the stent device and the host into which thedevice is implanted. In certain aspects, medical implants are providedthat include stents which are coated with a paclitaxel derivative or acomposition comprising a paclitaxel derivative which inhibits theformation of scar tissue. In another aspect, the stent may be adapted torelease a paclitaxel derivative which inhibits the formation of scartissue.

“Stent” refers to a device comprising a tube (composed of a metal,textile, non-degradable or degradable polymer, and/or other suitablematerial (such as biological tissue) which maintains flow of a fluid(e.g., blood) from one portion of a body passageway to another. In oneaspect, stents are or comprise scaffoldings that are used to treatendoluminal body passageways that have become blocked due to disease ordamage, including malignancy or benign disease. In another aspect, thetube has a generally cylindrical shape, such as to create and/ormaintain luminal patency of the body passageway. Representative examplesof stents, which are described in more detail below, include vascularstents, gastrointestinal stents, tracheal/bronchial stents,genital-urinary stents, and ENT stents.

Intravascular Stents

In one aspect, the present invention provides for the combination of apaclitaxel derivative or a composition comprising a paclitaxelderivative and an intravascular stent.

“Intravascular stent” or “vascular stent” as used herein refers to astent device that is implanted at least partially within the vasculature(e.g., blood vessels). In one aspect, an intravascular stent is anendovascular scaffolding which maintains the lumen of a body passageway(e.g., an artery) and allows bloodflow. In certain aspects, theintravascular stent may be a “coronary stent” (i.e., a stent that isused in the heart).

In one aspect, intravascular stents may comprise a generally cylindricaltube composed of a metal, textile, non-degradable or degradable polymer,and/or other suitable material (such as biological tissue) whichmaintains the flow of blood from one portion of a blood vessel toanother. Representative examples of intravascular stents that canbenefit from being coated with or having incorporated therein apaclitaxel derivative include coronary stents, peripheral stents, andcovered stents.

Vascular stents that can be used in the present invention includemetallic stents, polymeric stents, biodegradable stents and coveredstents. Stents may be self-expandable or balloon-expandable, composed ofa variety of metal compounds and/or polymeric materials, fabricated ininnumerable designs, used in coronary or peripheral vessels, composed ofdegradable and/or non-degradable components, fully or partially coveredwith vascular graft materials (so called “covered stents”) or “sleeves”,and can be bare metal or drug-eluting.

Stents may comprise a metal or metal alloy such as stainless steel,spring tempered stainless steel, stainless steel alloys, gold, platinum,super elastic alloys, cobalt-chromium alloys and other cobalt-containingalloys (including ELGILOY (Combined Metals of Chicago, Grove Village,IL), PHYNOX (Alloy Wire International, United Kingdom) and CONICHROME(Carpenter Technology Corporation, Wyomissing, PA)), titanium-containingalloys, platinum-tungsten alloys, nickel-containing alloys,nickel-titanium alloys (including nitinol), malleable metals (includingtantalum); a composite material or a clad composite material and/orother functionally equivalent materials; and/or a polymeric(non-biodegradable or biodegradable) material. Representative examplesof polymers that may be included in the stent construction includepolyethylene, polypropylene, polyurethanes, polyesters, such aspolyethylene terephthalate (e.g., DACRON or MYLAR (E. I. DuPont DeNemours and Company, Wilmington, DE)), polyamides, polyaramids (e.g.,KEVLAR from E. I. DuPont De Nemours and Company), polyfluorocarbons suchas poly(tetrafluoroethylene with and without copolymerizedhexafluoropropylene) (available, e.g., under the trade name TEFLON (E.I. DuPont De Nemours and Company)), silk, as well as the mixtures,blends and copolymers of these polymers. Stents also may be made withengineering plastics, such as thermotropic liquid crystal polymers(LCP), such as those formed from p,p′-dihydroxy-polynuclear-aromatics ordicarboxy-polynuclear-aromatics.

Further types of stents that can be used with the described therapeuticagents are described, e.g., in PCT Publication No. WO 01/01957 and U.S.Pat. Nos. 6,165,210; 6,099,561; 6,071,305; 6,063,101; 5,997,468;5,980,551; 5,980,566; 5,972,027; 5,968,092; 5,951,586; 5,893,840;5,891,108; 5,851,231; 5,843,172; 5,837,008; 5,766,237; 5,769,883;5,735,811; 5,700,286; 5,683,448; 5,679,400; 5,665,115; 5,649,977;5,637,113; 5,591,227; 5,551,954; 5,545,208; 5,500,013; 5,464,450;5,419,760; 5,411,550; 5,342,348; 5,286,254; and 5,163,952. Removabledrug-eluting stents are described, e.g., in Lambert, T. (1993) J. Am.Coli. Cardiol.: 21: 483A. Moreover, the stent may be adapted to releasethe desired agent at only the distal ends, or along the entire body ofthe stent.

Balloon over stent devices, such as are described in Wilensky, R.L.(1993) J. Am. Coll. Cardiol.: 21: 185A, also are suitable for localdelivery of a fibrosing agent to a treatment site.

In addition to using the more traditional stents, stents that arespecifically designed for drug delivery can be used. Examples of thesespecialized drug delivery stents as well as traditional stents includethose from Conor Medsystems (Palo Alto, CA) (e.g., U.S. Pat. Nos.6,527,799; 6,293,967; 6,290,673; 6,241,762; U.S. patent applicationPublication Nos. 2003/0199970 and 2003/0167085; and PCT Publication No.WO 03/015664).

Examples of intravascular stents, which may be combined with one or moretherapeutic agents according to the present invention, includecommercially available products. The stent may be self-expanding orballoon expandable (e.g., STRECKER stent by Medi-Tech/Boston ScientificCorporation), or implanted by a change in temperature (e.g., nitinolstent). Self-expanding stents that can be used include the coronaryWALLSTENT and the SCIMED RADIUS stent from Boston Scientific Corporation(Natick, Mass.) and the GIANTURCO stents from Cook Group, Inc.(Bloomington, Ind.). Examples of balloon expandable stents that can beused include the CROSSFLEX stent, BX-VELOCITY stent and thePALMAZ-SCHATZ crown and spiral stents from Cordis Corporation (MiamiLakes, Fla.), the V-FLEX PLUS stent by Cook Group, Inc., the NIR,EXPRESS and LIBRERTE stents from Boston Scientific Corporation, the ACSMULTI LINK, MULTI LINK PENTA, SPIRIT, and CHAMPION stents from GuidantCorporation, and the Coronary Stent S670 and S7 by Medtronic, Inc.(Minneapolis, Minn.).

Other examples of stents that can be combined with a fibrosing agent inaccordance with the invention include those from Boston ScientificCorporation, (e.g., the drug-eluting TAXUS EXPRESS² Paclitaxei-EiutingCoronary Stent System; over the wire stents such as the Express²Coronary Stent System and NIR Elite OTW Stent System; rapid exchangestents such as the EXPRESS² Coronary Stent System and the NIR ELITEMONORAIL Stent System; and self-expanding stents such as the MAGICWALLSTENT Stent System and RADIUS Self Expanding Stent); Medtronic, Inc.(Minneapolis, Minn.) (e.g., DRIVER ABT578-eluting stent, DRIVER ZIPPERMX MultiExchange Coronary Stent System and the DRIVER Over-the-WireCoronary Stent System; the S7 ZIPPER MX Multi-Exchange Coronary StentSystem; S7, S670, S660, and BESTENT2 with Discrete TechnologyOver-the-Wire Coronary Stent System); Guidant Corporation (e.g., cobaltchromium stents such as the MULTI-LINK VISION Coronary Stent System;MULTI-LINK ZETA Coronary Stent System; MULTI-LINK PIXEL Coronary StentSystem; MULTI-LINK ULTRA Coronary Stent System; and the MULTI-LINKFRONTIER); Johnson & Johnson/Cordis Corporation (e.g., CYPHERsirolimus-eluting Stent; PALMAZ-SCHATZ Balloon Expandable Stent; andS.M.A.R.T. Stents); Abbott Vascular (Redwood City, Calif.) (e.g., MATRIXLO Stent; TRIMAXX Stent; and DEXAMET stent); Goner Medsystems (MenloPark, Calif.) (e.g., MEDSTENT and COSTAR stent); AMG GmbH (Germany)(e.g., PICO Elite stent); Biosensors International (Singapore) (e.g.,MATRIX stent, CHAMPION Stent (formerly the S-STENT), and CHALLENGEStent); Biotronik (Switzerland) (e.g., MAGIC AMS stent); ClearstreamTechnologies (Ireland) (e.g., CLEARFLEX stent); Cook Inc. (Bloomington,Ind.) (e.g., V-FLEX PLUS stent, ZILVER PTX self-expanding vascular stentcoating, LOGIX PTX stent (in development); Devax (e.g., AXXESS stent)(Irvine, CA); DISA Vascular (Pty) Ltd (South Africa) (e.g., CHROMOFLEXStent, S-FLEX Stent, S-FLEX Micro Stent, and TAXOCHROME DES); lntekTechnology (Baar, Switzerland) (e.g., APOLLO stent); Orbus MedicalTechnologies (Hoevelaken, The Netherlands) (e.g., GENOUS); SorinBiomedica (Saluggia, Italy) (e.g., JANUS and CARBOSTENT); and stentsfrom Bard/Angiomed GmbH Medizintechnik KG (Murray Hill, N.J.), and BlueMedical Supply & Equipment (Mariettta, Ga.), Aachen Resonance GmbH(Germany); Eucatech AG (Germany), Eurocor GmbH (Bonn, Germany), Prot,Goodman, Terumo (Japan), Translumina GmbH (Germany), MIV Therapeutics(Canada), Occam International B.V. (Eindhoven, The Netherlands),Sahajanand Medical Technologies PVT LTD. (India); AVIBiopharma/Medtronic/ lnterventional Technologies (Portland, Ore.) (e.g.,RESTEN NG-coated stent); and Jomed (e.g., FLEXMASTER drug-eluting stent)(Sweden).

Gastrointestinal Stents

In another aspect, the present invention provides for the combination ofa paclitaxel derivative and a gastrointestinal (GI) stent.Gastrointestinal stent devices may be positioned in various parts of thegastrointestinal tract including the biliary duct, pancreatic duct,colon, and the esophagus. GI stents are or comprise scaffoldings thatare used to treat endoluminal body passageways (e.g., esophagus, colon,bile duct, pancreatic duct, and the like) that have become blocked dueto disease or damage, including malignancy or benign disease.

In one aspect, the GI stent may be an esophageal stent used to keep theesophagus open whereby food is able to travel from the mouth to thestomach. For example, the esophageal stent may be composed of acylindrical supporting mesh inner layer, retaining mesh outer layer anda semi-permeable membrane sandwiched between. See, e.g., U.S. Pat. No.6,146,416. The esophageal stent may be a radially, self-expanding stentof open weave construction with an elastomeric film formed along thestent to prevent tissue ingrowth and distal cuffs that resist stentmigration. See, e.g., U.S. Pat. No. 5,876,448. The esophageal stent maybe composed of a flexible wire configuration to form a cylindrical tubewith a deformed end portion increased to a larger diameter for anchoringpressure. See, e.g., U.S. Pat. No. 5,876,445. The esophageal stent maybe a flexible, self-expandable tubular wall incorporating at least onetruncated conical segment along the longitudinal axis. See, e.g., U.S.Pat. No. 6,533,810.

In another aspect, the Gl stent may be a biliary stent used to keep thebiliary duct open whereby bile is able to drain into the smallintestines. For example, the biliary stent may be composed of shapememory alloy. See, e.g., U.S. Pat. No. 5,466,242. The biliary stent maybe a plurality of radially extending wings with grooves which projectfrom a helical core. See, e.g., U.S. Pat. Nos. 5,776,160 and 5,486,191.

In another aspect, the GI stent may be a colonic stent. For example, thecolonic stent may be a hollow tubular body that may expand radially andbe secured to the inner wall of the organ in a release fitting. See,e.g., European Patent Application No. EP1092400A2.

In another aspect, the GI stent may be a pancreatic stent used to keepthe pancreatic duct open to facilitate secretion into the smallintestines. For example, the pancreatic stent may be composed of a softbiocompatible material which is resiliently compliant which conforms tothe duct's curvature and contains perforations that facilitatesdrainage. See, e.g., U.S. Pat. No. 6,132,471.

GI stents, which may be combined with one or more drugs according to thepresent invention, include commercially available products, such as theNIR Biliary Stent System and the WALLSTENT Endoprostheses from BostonScientific Corporation.

Tracheal and Bronchial Stents

In another aspect, the present invention provides for the combination ofa paclitaxel derivative and a tracheal or bronchial stent device.

Representative examples of tracheal or bronchial stents that can benefitfrom being coated with or having incorporated therein a paclitaxelderivative include metallic and polymeric tracheal or bronchial stentsand tracheal or bronchial stents that have an external covering (e.g.,polyurethane, poly(ethylene terephthalate), PTFE, or silicone rubber).

Tracheal and bronchial stents may be, for example, composed of anelastic plastic shaft with metal clasps that expands to form a lumenalong the axis for opening the diseased portion of the trachea andhaving three sections to emulate the natural shape of the trachea. See,e.g., U.S. Pat. No. 5,480,431. The tracheal/bronchial stent may be aT-shaped tube having a tracheotomy tubular portion that projectsoutwardly through a tracheotomy orifice which is configured to close andform a fluid seal. See, e.g., U.S. Pat. Nos. 5,184,610 and 3,721,233.The tracheal/bronchial stent may be composed of a flexible, syntheticpolymeric resin with a tracheotomy tube mounted on the wall with abifurcated bronchial end that is configured in a T-Y shape with specificcurves at the intersections to minimize tissue damage. See, e.g., U.S.Pat. No. 4,795,465. The tracheal/bronchial stent may be a scaffoldingconfigured to be substantially cylindrical with a shape-memory framehaving geometrical patterns and having a coating of sufficient thicknessto prevent epithelialization. See, e.g., U.S. patent applicationPublication No. 2003/0024534A1.

Tracheal and bronchial stents, which may be combined with one or moreagents according to the present invention, include commerciallyavailable products, such as the WALLSTENT TracheobronchialEndoprostheses and ULTRAFLEX Tracheobronchial Stent Systems from BostonScientific Corporation and the DUMON Tracheobronchial Silicone Stentsfrom Bryan Corporation (Woburn, Mass.).

Genital-Urinary Stents

In another aspect, the present invention provides for the combination ofa paclitaxel derivative and genital-urinary (GU) stent device.

Representative examples genital-urinary (GU) stents that can benefitfrom being coated with or having incorporated therein, a paclitaxelderivative include ureteric and urethral stents, fallopian tube stents,prostate stents, including metallic and polymeric GU stents and GUstents that have an external covering (e.g., polyurethane, poly(ethyleneterephthalate), PTFE or silicone rubber).

In one aspect, genital-urinary stents include ureteric and urethralstents. Ureteral stents are hollow tubes with holes along the sides andcoils at either end to prevent migration. Ureteral stents are used torelieve obstructions (caused by stones or malignancy), to facilitate thepassage of stones, or to allow healing of ureteral anastomoses or leaksfollowing surgery or trauma. They are placed endoscopically via thebladder or percutaneously via the kidney.

Urethral stents are used for the treatment of recurrent urethralstrictures, detruso-external sphincter dyssynergia and bladder outletobstruction due to benign prostatic hypertrophy. In addition, proceduresthat are conducted for the prostate, such as external radiation orbrachytherapy, may lead to fibrosis due to tissue insult resulting fromthese procedures. The incidence of urethral stricture in prostate cancerpatients treated with external beam radiation is about 2%. Developmentof urethral stricture may also occur in other conditions such asfollowing urinary catheterization or surgery, which results in damage tothe epithelium of the urethra. The clinical manifestation of urinarytract obstruction includes decreased force and caliber of the urinarystream, intermittency, postvoid dribbling, hesitance and nocturia.Complete closure of the urethra can result in numerous problemsincluding eventual kidney failure. To maintain patency in the urethra,urethral stents may be used. The stents are typically self-expanding andcomposed of metal superalloy, titanium, stainless steel or polyurethane.

For example, the ureteric/urethral stent may be composed of a maincatheter body of flexible polymeric material having an enlarged entryend with a hydrophilic tip that dissolves when contacted with bodyfluids. See, e.g., U.S. Pat. No. 5,401,257. The ureteric/urethral stentmay be composed of a multi-sections including a closed section at thatthe bladder end which does not contain any fluid passageways such thatit acts as an anti-reflux device to prevent reflux of urine back intothe kidney. See, e.g., U.S. Pat. No. 5,647,843. The ureteric/urethralstent may be composed of a central catheter tube made of shape memorymaterial that forms a stent with a retention coil for anchoring to theureter. See, e.g., U.S. Pat. No. 5,681,274. The ureteric/urethral stentmay be a composed of an elongated flexible tubular stent with preformedset curls at both ends and an elongated tubular rigid extension attachedto the distal end which allows the combination function as anexternalized ureteral catheter. See, e.g., U.S. Pat. Nos. 5,221,253 and5,116,309. The ureteric/urethral stent may be composed of an elongatedmember, a proximal retention structure, and a resilient portionconnecting them together, whereby they are all in fluid communicationwith each other with a slideable portion providing a retracted andexpanded position. See, e.g., U.S. Pat. No. 6,685,744. Theureteric/urethral stent may be a hollow cylindrical tube that has aflexible connecting means and locating means that expands andselectively contracts. See, e.g., U.S. Pat. No. 5,322,501. Theureteric/urethral stent may be composed of a stiff polymeric body thataffords superior columnar and axial strength for advancement into theureter, and a softer bladder coil portion for reducing the risk ofirritation. See, e.g., U.S. Pat. No. 5,141,502. The ureteric/urethralstent may be composed of an elongated tubular segment that has a pliablewall at the proximal region and a plurality of members that preventblockage of fluid drainage upon compression. See, e.g., U.S. Pat. No.6,676,623. The ureteric/urethral stent may be a catheter composed of aconduit which is part of an assembly that allows for non-contaminatedinsertion into a urinary canal by providing a sealing member thatsurrounds the catheter during dismantling. See, e.g., U.S. PatentApplication Publication No. 2003/0060807A1.

In another aspect, genital-urinary stents include prostatic stents. Forexample, the prostatic stent may be composed of two polymeric ringsconstructed of tubing with a plurality of connecting arm membersconnecting the rings in a parallel manner. See, e.g., U.S. Pat. No.5,269,802. The prostatic stent may be composed of thermoplastic materialand a circumferential reinforcing helical spring, which provides rigidmechanical support while being flexible to accommodate the naturalanatomical bend of the prostatic urethra. See, e.g., U.S. Pat. No.5,069,169.

In another aspect, genital-urinary stents include fallopian stents andother female genital-urinary devices. For example, the genital-urinarydevice may be a female urinary incontinence device composed of avaginal-insertable supporting portion that is resilient and flexible,which is capable of self-support by expansion against the vaginal walland extending about the urethral orifice. See, e.g., U.S. Pat. No.3,661,155. The genital-urinary device may be a urinary evacuation devicecomposed of an ovular bulbous concave wall having an opening to a bodyengaging perimetal edge integral with the wall and an attached tubularmember with a pleated body. See, e.g., U.S. Pat. No. 6,041,448.

Genital-urinary stents, which may be combined with one or more agentsaccording to the present invention, include commercially availableproducts, such as the UROLUME Endoprosthesis Stents from AmericanMedical Systems, Inc. (Minnetonka, Minn.), the RELIEVEProstatic/Urethral Endoscopic Device from InjecTx, Inc. (San Jose,Calif.), the PERCUFLEX Ureteral Stents from Boston ScientificCorporation, and the TARKINGTON Urethral Stents and FIRLIT-KLUGEUrethral Stents from Cook Group Inc (Bloomington, Ind.).

Ear and Nose Stents

The present invention provides for the combination of a paclitaxelderivative and an ear-nose-throat (ENT) stent device (e.g., a lacrimalduct stent, Eustachian tube stent, nasal stent, or sinus stent).

The sinuses are four pairs of hollow regions contained in the bones ofthe skull named after the bones in which they are located (ethmoid,maxillary, frontal and sphenoid). All are lined by respiratory mucosawhich is directly attached to the bone. Following an inflammatory insultsuch as an upper respiratory tract infection or allergic rhinitis, apurulent form of sinusitis can develop. Occasionally secretions can beretained in the sinus due to altered ciliary function or obstruction ofthe opening (ostea) that drains the sinus. Incomplete drainage makes thesinus prone to infection typically with Haemophilus influenza,Streptococcus pneumoniae, Moraxella catarrhalis, Veillonella,Peptococcus, Corynebacterium acnes and certain species of fungi.

When initial treatment such as antibiotics, intranasal steroid spraysand decongestants are ineffective, it may become necessary to performsurgical drainage of the infected sinus. Surgical therapy often involvesdebridement of the ostea to remove anatomic obstructions and removal ofparts of the mucosa. Occasionally a stent (a cylindrical tube whichphysically holds the lumen of the ostea open) is left in the osta toensure drainage is maintained even in the presence of postoperativeswelling. ENT stents, typically made of stainless steel or plastic,remain in place for several days or several weeks before being removed.

Representative examples of ENT stents that can benefit from being coatedwith or having incorporated therein a paclitaxel derivative includelacrimal duct stents, Eustachian tube stents, nasal stents, and sinusstents.

In one aspect, the present invention provides for the combination of alacrimal duct stent and a paclitaxel derivative or a compositioncomprising a paclitaxel derivative.

In another aspect, the present invention provides for the combination ofa Eustachian tube stent and a paclitaxel derivative or a compositioncomprising a paclitaxel derivative.

In yet another aspect, the present invention provides for thecombination of a sinus stent and a paclitaxel derivative or acomposition comprising a paclitaxel derivative. Representative examplesof sinus stents include the FREEMAN Frontal Sinus Stent (Head and NeckSurgery Associates, Indianapolis, IN) and the PARRELL Frontal SinusT-Stent 15-15000.

In yet another aspect, the present invention provides for thecombination of a nasal stent and a paclitaxel derivative or acomposition comprising a paclitaxel derivative.

The ENT stent may be a choanal atresia stent composed of two long hollowtubes that are bridged by a flexible transverse tube. See, e.g., U.S.Pat. No. 6,606,995. The ENT stent may be an expandable nasal stent forpostoperative nasal packing composed of a highly porous, pliable andabsorbent foam material capable of expanding outwardly, which has anonadherent surface. See, e.g., U.S. Pat. No. 5,336,163. The ENT stentmay be a nasal stent composed of a deformable cylinder with a breathingpassageway that has a smooth outer non-absorbent surface used forpacking the nasal cavity following surgery. See, e.g., U.S. Pat. No.5,601,594. The ENT stent may be a ventilation tube composed of aflexible, plastic, tubular vent with a rectangular flexible flange whichis used for the nasal sinuses following endoscopic antrostomy. See,e.g., U.S. Pat. No. 5,246,455. The ENT stent may be a ventilating eartube composed of a shaft and an extended tab which is used forequalizing the pressure between the middle ear and outer ear. See, e.g.,U.S. Pat. No. 6,042,574. The ENT stent may be a middle ear vent tubecomposed of a non-compressible, tubular base and an eccentric flange.See, e.g., U.S. Pat. No. 5,047,053.

ENT stents, which may be combined with one or more agents according tothe present invention, include commercially available products such asthe SEPRAGEL stent and SEPRAPACK bioresorbable nasal packing and sinusstent from Genzyme Corporation (Ridgefield, N.J.), MEROGEL Sinus Stentsfrom Medtronic Xomed Surgical Products, Inc. (Jacksonville, Fla.),SINUS-FLEX stents from Optimed (Germany), the OXYCELL nasal sinus stentfrom GMP Companies Inc., the SURGICELL nasal/sinus stent from Ethicon,Inc., and the RAINS Frontal Sinus Stent (see, U.S. Pat. No. 5,693,065)sold by the Smith & Nephew.

B. Therapeutic Agents

Suitable fibrosis or stenosis-inhibiting paclitaxel derivatives may bereadily determined based upon the in vitro and in vivo (animal) modelssuch as those provided in Examples 26-36.

Numerous paclitaxel derivatives may be used to inhibit fibrosis in thevicinity of a stent in accordance with the invention. “Paclitaxelderivatives” as used herein includes compounds that structurally similarto paclitaxel but differ slightly in composition (e.g., one atom orfunctional group is different, added or removed), compounds that arestructurally similar to paclitaxel and either actually or theoreticallyderivable from paclitaxel, conjugates of paclitaxel (e.g.,paclitaxel-PEG, paclitaxel-dextran, and paclitaxel-xylos), inactiveforms of paclitaxel that may be converted into an active form ofpaclitaxel under physiological conditions, solvates (e.g., hydrates oradducts) of paclitaxel, active metabolites of paclitaxel, and salts ofpaclitaxel.

Paclitaxel is a compound which disrupts mitosis (M-phase) by binding totubulin to form abnormal mitotic spindles or an analogue or derivativethereof. Briefly, paclitaxel is a highly derivatized diterpenoid (Waniet al, J. Am. Chem. Soc. 93:2325, 1971) which has been obtained from theharvested and dried bark of Taxus brevifolia (Pacific Yew) and TaxomycesAndreanae and Endophytic Fungus of the Pacific Yew (Stierle et al.,Science 60:214-216, 1993).

Paclitaxel and its derivatives are considered to function as cell cycleinhibitors by acting as anti-microtubule agents, and more specificallyas a microtubule stabilizer. These compounds have been shown useful inthe treatment of proliferative disorders, including: non-small cell(NSC) lung; small cell lung; breast; prostate; cervical; endometrial;head and neck cancers.

Representative examples of paclitaxel derivatives that may be used incombination with stents in accordance with the invention includedocetaxol (TAXOTERE from Aventis Pharmaceuticals, France), 10-desacetylanalogues of paclitaxel and 3′N-desbenzoyl-3′-N-t-butoxy carbonylanalogues of paclitaxel, 7-deoxy-docetaxol, 7,8-cyclopropataxanes,N-substituted 2-azetidones, 6,7-epoxy paclitaxels, 6,7-modifiedpaclitaxels, 10-desacetoxytaxol, 10-deacetyltaxol (from10-deacetylbaccatin III), phosphonooxy and carbonate derivatives oftaxol, taxol 2′,7-di(sodium) 1,2-benzenedicarboxylate,10-desacetoxy-11,12-dihydrotaxol-10,12(18)-diene derivatives,10-desacetoxytaxol, protaxol (2′-and/or 7-O-ester derivatives),(2′-and/or 7-O-carbonate derivatives), asymmetric synthesis of taxolside chain, fluoro taxols, 9-deoxotaxane,N-debenzoyl-N-tert-(butoxycaronyl)-10-deacetyltaxol,13-acetyl-9-deoxobaccatine III, derivatives containing hydrogen oracetyl group and a hydroxy and tert-butoxycarbonylamino, sulfonated2′-acryloyltaxol and sulfonated 2′-O-acyl acid taxol derivatives,succinyltaxol, 2′-γ-aminobutyryltaxol formate, 2′-acetyl taxol, 7-acetyltaxol, 7-glycine carbamate taxol, 2′-OH-7-PEG(5000) carbamate taxol,2′-benzoyl and 2′,7-dibenzoyl taxol derivatives, other prodrugs(2′-acetyltaxol; 2′,7-diacetyltaxol; 2′-succinyltaxol;2′-(beta-alanyl)-taxol); 2′-gamma-aminobutyryltaxol formate; ethyleneglycol derivatives of 2′-succinyltaxol; 2′-glutaryltaxol;2′-(N,N-dimethylglycyl) taxol; 2′-(2-(N,N-dimethylamino)propionyl)taxol;2′-orthocarboxybenzoyl taxol; 2′-aliphatic carboxylic acid derivativesof taxol, 2′-(N,N-diethylaminopropionyl)taxol,2′-(N,N-dimethylglycyl)taxol, 7-(N,N-dimethylglycyl)taxol, 2′,7-di-(N,N-dimethylglycyl)taxol, 7-(N,N-diethylaminopropionyl)taxol, 2′,7-di(N, N-diethylaminopropionyl)taxol, 2′-(L-glycyl)taxol,7-(L-glycyl)taxol, 2′, 7-di(L-glycyl)taxol, 2′-(L-alanyl)taxol,7-(L-alanyl)taxol, 2′,7-di(L-alanyl)taxol, 2′-(L-leucyl)taxol,7-(L-leucyl)taxol, 2′,7-di(L-leucyl)taxol, 2′-(L-isoleucyl)taxol,7-(L-isoleucyl)taxol, 2′, 7-di(L-isoleucyl)taxol, 2′-(L-valyl)taxol,7-(L-valyl)taxol, 2′7-di(L-valyl)taxol, 2′-(L-phenylalanyl)taxol,7-(L-phenylalanyl)taxol, 2′,7-di(L-phenylalanyl)taxol,2′-(L-prolyl)taxol, 7-(L-prolyl)taxol, 2′,7-di(L-prolyl)taxol,2′-(L-lysyl)taxol, 7-(L-lysyl)taxol, 2′, 7-di(L-lysyl)taxol,2′-(L-glutamyl)taxol, 7-(L-glutamyl)taxol, 2′,7-di(L-glutamyl)taxol,2′-(L-arginyl)taxol, 7-(L-arginyl)taxol, 2′,7-di(L-arginyl)taxol, taxolanalogues with modified phenylisoserine side chains, debenzoyl-2-acylpaclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxyand carbonate paclitaxel derivatives, sulfonated 2′-acryloyltaxol;sulfonated 2′-O-acyl acid paclitaxel derivatives, 18-site-substitutedpaclitaxel derivatives, chlorinated paclitaxel analogues, C4 methoxyether paclitaxel derivatives, brominated paclitaxel analogues,nitrophenyl paclitaxel, 10-deacetylated substituted paclitaxelderivatives, 2-debenzoyl and-2-acyl paclitaxel derivatives, n-acylpaclitaxel derivatives, 10-deacetylbaccatin III and7-protected-10-deacetylbaccatin III derivatives from 10-deacetyl taxolA, 10-deacetyl taxol B, and 10-deacetyl taxol, benzoate derivatives oftaxol, 2-aroyl-4-acyl paclitaxel analogues, orthro-ester paclitaxelderivatives, 2-aroyl-4-acyl paclitaxel and 1-deoxy paclitaxel and1-deoxy paclitaxel derivatives, and3′-desphenyl-3′-(4-ntirophenyl)-N-debenzoyl-N-(t-butoxycarbonyl)-10-deacetyltaxol.

Paclitaxel derivatives for use in combination with a stent include thoseprepared from 9-deoxygenated taxane compounds having the structure (C1):

wherein X is be hydrogen (9-deoxy derivatives), thioacyl, or dihydroxylprecursors; R₁ is alkanoyl or a radical of the formula (C2)

wherein R₇ is selected from hydrogen, alkyl, phenyl (substituted orunsubstituted), alkoxy (substituted or unsubstituted), amino(substituted or unsubstituted), phenoxy (substituted or unsubstituted);R₈ is selected from hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, phenyl (substituted or unsubstituted), alpha orbeta-naphthyl; and R₉ is selected from hydrogen, alkanoyl, substitutedalkanoyl, and aminoalkanoyl; where substitutions refer to hydroxyl,sulfhydryl, allalkoxyl, carboxyl, halogen, thioalkoxyl,N,N-dimethylamino, alkylamino, dialkylamino, nitro, and —OS)₃H, and/ormay refer to groups containing such substitutions; R₂ is selected fromhydrogen or oxygen-containing groups, such as hydroxyl, alkoyl,alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy; R₃ is selectedfrom hydrogen or oxygen-containing groups, such as hydroxyl, alkoyl,alkanoyloxy, aminoalkanoyloxy, and peptidyalkanoyloxy, and may furtherbe a silyl containing group or a sulphur containing group; R₄ isselected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl andaroyl; R₅ is selected from acyl, alkyl, alkanoyl, aminoalkanoyl,peptidylalkanoyl and aroyl; R₆ is selected from hydrogen oroxygen-containing groups, such as hydroxyl alkoyl, alkanoyloxy,aminoalkanoyloxy, and peptidyalkanoyloxy (see, e.g., U.S. Pat. No.5,440,056).

Examples of paclitaxel derivatives prepared from the 9-deoxygenatedtaxane compounds having the structure (C2) include 9-deoxotaxol,7-deoxy-9-deoxotaxol, and 10-desacetoxy-7-deoxy-9-deoxotaxol.

In one aspect, the paclitaxel derivative may be a 9-dihydrotaxolderivative having the structure (C3) prepared from9-dihydro-13-acetylbaccatin III,

wherein R¹ is a group having the formula:

wherein R⁸ is hydrogen, alkyl, phenyl(substituted or unsubstituted),alkoxy (substituted or unsubstituted), amino (substituted orunsubstituted), or phenoxy (substituted or unsubstituted).

R², R⁴, R⁵ and R⁷ in structure (C3) are independently hydrogen, alkyl,alkanoyl, or aminoalkanoyl.

R³ in structure (C3) is hydrogen, alkyl, or aminoalkanoyl.

R⁶ in structure (C3) is hydrogen, alkyl, alkanoyl, aminoalkanoyl, orphenylcarbonyl (—C(O)-phenyl).

Alternatively, R³ in structure (C3), taken together with either R² orR⁴, may form a ring having the formula

wherein R¹¹ and R¹² are independently hydrogen, alkyl, phenyl orsubstituted phenyl; or, taken together, R¹¹ and R¹² are a single atomselected from the group consisting of oxygen and sulfur; or one of R¹¹and R¹² is hydrogen, alkyl, phenyl (substituted or unsubstituted), andthe other is —OR¹³ or —NR¹³R¹⁴ where R¹³ and R¹⁴ are independentlyalkyl, alkanoyl, substituted alkanoyl, phenyl or substituted phenyl.

Examples of paclitaxel derivatives prepared from the compounds havingthe structure (C3) include 9-dihydrotaxol compounds (R³ of structure C3is hydrogen).

In one aspect, the paclitaxel derivative is 9-dihydrotaxol (R² and R⁵are acetyl; R³, R⁴, and R⁷ are hydrogen, and R⁶ is phenylcarbonyl).

In another aspect, the 9-dihydrotaxol compound is2′-O-ethoxyethyl-7-O-trietylsilyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound is2′-O-ethoxyethyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound is10-deacetyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7,9-isopropylidene ketal.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7,9-propylidene acetal.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7,9-benzylidene acetal.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7,9-(3,4-dihydroxy)butylidene acetal.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7,9-thionocarbonate.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7-O-allyl ether.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7-O-(2,3-dihydroxypropyl) ether.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7-O-(2-dimethylaminoethyl) ether.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7-O-(2-hydroxyethyl) ether.

In another aspect, the 9-dihydrotaxol compound is9-dihydrotaxol-7-O-(2-acetoxyethyl) ether.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound is10-deacetyi-N-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-t-butylacetyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-isobutoxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-adamantoxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-isopropoxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-benzyloxycarbonyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-pivaloyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-acetyl-9-dihydrotaxol.

In another aspect, the 9-dihydrotaxol compound isN-debenzoyl-N-t-butylcarbamyl-9-dihydrotaxol.

In another aspect, the paclitaxel derivative may be prepared from a9-dihydropaclitaxel derivative, such as 9-dihydro-13-acetylbaccatin III(see, e.g., U.S. Pat. No. 5,468,769).

In one aspect, the paclitaxel derivative is2′-O-(1-ethyoxyethyl)-9-dihydrotaxol.

In one aspect, the paclitaxel derivative is4,9,12-tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete.

In another aspect, the paclitaxel derivative isβ-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-yl ester.

In another aspect, the paclitaxel derivative isβ-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.

Additional examples of paclitaxel derivatives that may be used in thepractice of the invention include the following:

4,9,12(tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate;

4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[-1,2-b]oxete-8methylphosphate;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-1-undecahydro-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl1-,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate;

4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylphosphate;

4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cycionona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester;

1,3-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methyihydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yi)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyioxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyioxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-yl ester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b)oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17otetramethyl-1,10-methano-20H-cyclonona(2,3]benz[1,2-b]oxet-12-yl ester;

β-benzoylamino-α-hydroxy-γ-(1-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxy-γ-(2-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxy-γ-(pyridyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-tert-benzoylamino-α-hydroxy-γ-(thienyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxy-γ-(furyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxy-γ-(oxazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-yl ester;

β-benzoylamino-α-hydroxy-γ-(imidazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

β-benzoylamino-α-hydroxy-γ-(pyrazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester;

and

β-benzoylamino-α-hydroxy-γ-(pyridazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester,

as well as prodrugs thereof.

Although the above therapeutic agents have been provided for thepurposes of illustration, it should be understood that the presentinvention is not so limited. Further, more than one therapeutic agentmay be utilized at a time (i.e., in combination), or deliveredsequentially.

C. Methods for Combining Stents with Paclitaxel Derivatives

In the practice of this invention, drug-coated or drug-impregnatedimplants and medical devices are provided which inhibit fibrosis in andaround the device, or prevent “stenosis” of the device/implant in situ,thus enhancing the efficacy. Within various embodiments, fibrosis isinhibited by local or systemic release of specific pharmacologicalagents that become localized to the tissue adjacent to the device orimplant. There are numerous methods available for optimizing delivery ofthe paclitaxel derivative to the site of the intervention and several ofthese are described below.

In one aspect, the present invention provides stents which comprise apaclitaxel derivative which inhibits fibrosis on at least one surfaceof, or around, the medical device once deployed in the patient. Incertain embodiments, the stent device may be adapted to release theagent upon deployment of the device in the patient. The paclitaxelderivative may be released from all or only a portion of the stent. Forexample, the derivative may be released at only the distal ends or alongthe entire body of the device. Paclitaxel derivatives may be associatedwith stents in a variety of manners, including by (a) directly affixingto the implant or device a desired therapeutic agent or compositioncontaining the therapeutic agent (e.g:, by either spraying orelectrospraying the medical implant with a drug and/or carrier(polymeric or non-polymeric)-drug composition to create a film and/orcoating on all, or part of an internal or external surface of thedevice; by dipping the implant or device into a drug and/or carrier(polymeric or non-polymeric)-drug solution to coat all or part of thedevice or implant; or by other covalent or noncovalent attachment of thetherapeutic agent to the device or implant surface); (b) by coating themedical device or implant with a substance such as a hydrogel whicheither contains or which will in turn absorb the desired paclitaxelderivative or composition; (c) by interweaving a “thread” comprised of apaclitaxel derivative into the medical implant or device (e.g., apolymeric strand comprised of a paclitaxel derivative composition) orpolymers which release a paclitaxel derivative from the thread); (d) bycovering all, or a portion of the device or implant with a sleeve,cover, electrospun fabric or mesh comprising a paclitaxel derivative(i.e., a covering comprised of a paclitaxel derivative—a paclitaxelderivative or polymerized composition containing paclitaxelderivatives); (e) constructing all, or part of the device or implantitself with the desired agent or composition (e.g., a paclitaxelderivative or polymerized compositions of paclitaxel derivatives); (f)otherwise impregnating the device or implant with a desired paclitaxelderivative or composition; (g) composing all, or part, of the device orimplant from a metal alloy that inhibits fibrosis; (h) utilizingspecialized multi-drug releasing medical device systems (for example,U.S. Pat. Nos. 6,527,799; 6,293,967; 6,290,673; 6,241,762, U.S.Application Publication Nos. 2003/0199970A1 and 2003/0167085A1; and PCTPublication WO 03/015664) to deliver paclitaxel derivatives alone or incombination; and (i) constructing all, or part of the device or implantitself from a degradable or non-degradable polymer that is capable ofreleasing one or more paclitaxel derivatives (e.g., the paclitaxelderivative can be combined with the materials that are used to make thedevice such that the paclitaxel derivative is incorporated into thefinal device; this can include the stent structure itself, the outercovering or sleeve, if applicable, or both the stent structure and theouter covering or sleeve).

1) Coating of Stents with Paclitaxel Derivatives

As described above, a range of polymeric and non-polymeric materials canbe used to incorporate the paclitaxel derivative onto or into a device.Coating of the device with the paclitaxel derivative or a compositionthat comprises the paclitaxel derivative is one method that may be usedto associate the agent with the device. The anti-fibrosing agent oranti-fibrosing composition may be coated onto the entire device or aportion of the device using a method such as dipping, spraying, paintingor vacuum deposition that is appropriate for the particular type ofdevice. For these devices, the coating process can be performed in sucha manner as to (a) coat the external surface of the stent, (b) coat theinternal (luminal) surface of the stentor (c) coat all or parts of boththe internal and external surfaces of the stent.

a) Dip coating

Dip coating is one coating process that can be used. In one embodiment,the paclitaxel derivative is dissolved in a solvent for the fibrosisagent and is then coated onto the device.

Paclitaxel derivative with an inert-solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be immersed, either partially or completely, in the paclitaxelderivative/solvent solution for a specific period of time. The rate ofimmersion into the paclitaxel derivative/solvent solution can be altered(e.g., 0.001 cm per sec to 50 cm per sec). The device can then beremoved from the solution. The rate at which the device can be withdrawnfrom the solution can be altered (e.g., 0.001 cm per sec to 50 cm persec). The coated device can be air-dried. The dipping process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess will result in the paclitaxel derivative being coated on thesurface of the device.

Paclitaxel derivative with a swelling solvent

In one embodiment, the solvent is one that will not dissolve the devicebut will be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be immersed, either partially orcompletely, in the paclitaxel derivative/solvent solution for a specificperiod of time (seconds to days). The rate of immersion into thepaclitaxel derivative/solvent solution can be altered (e.g., 0.001 cmper sec to 50 cm per sec). The device can then be removed from thesolution. The rate at which the device can be withdrawn from thesolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thecoated device can be air-dried. The dipping process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. This process willresult in the paclitaxel derivative being adsorbed into the medicaldevice. The paclitaxel derivative may also be present on the surface ofthe device. The amount of surface associated paclitaxel derivative maybe reduced by dipping the coated device into a solvent for thepaclitaxel derivative or by spraying the coated device with a solventfor the paclitaxel derivative.

Paclitaxel derivative with a solvent

In one embodiment, the solvent is one that will be absorbed by thedevice and that will dissolve the device. The device can be immersed,either partially or completely, in the paclitaxel derivative/solventsolution for a specific period of time (seconds to hours). The rate ofimmersion into the paclitaxel derivative/solvent solution can be altered(e.g., 0.001 cm per sec to 50 cm per sec). The device can then beremoved from the solution. The rate at which the device can be withdrawnfrom the solution can be altered (e.g., 0.001 cm per sec to 50 cm persec). The coated device can be air-dried. The dipping process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Thisprocess will result in the paclitaxel derivative being adsorbed into themedical device as well as being surface associated. In a preferredembodiment, the exposure time of the device to the solvent can be suchthat there are no significant permanent dimensional changes to thedevice. The paclitaxel derivative may also be present on a surface ofthe device. The amount of surface associated paclitaxel derivative maybe reduced by dipping the coated device into a solvent for thepaclitaxel derivative or by spraying the coated device with a solventfor the paclitaxel derivative.

In the above description the device can be a device that has not beenmodified as well as a device that has been further modified byassociation with a polymer, surface treated by plasma treatment, flametreatment, corona treatment, surface oxidation or reduction, surfaceetching, mechanical smoothing or roughening, or grafting prior to theaffixing process.

In one embodiment, the paclitaxel derivative and a polymer are dissolvedin a solvent, for both the polymer and the fibrosis-inhibiting agent,and are then coated onto the device, together or separately.

In any one of the above dip coating methods, the surface of the devicecan be treated with a plasma polymerization method prior to coating ofthe scarring agent or scarring agent containing composition, such that athin polymeric layer is deposited onto a surface of the device. Examplesof such methods include parylene coating of devices and the use ofvarious monomers such hydrocyclosiloxane monomers. Parylene coating maybe especially advantageous if the device, or a portion of the device, iscomposed of materials (e.g., stainless steel, nitinol) that do not allowincorporation of the therapeutic agent(s) into a surface using one ofthe above methods. A parylene primer layer may be deposited onto thedevice using a parylene coater (e.g., PDS 2010 LABCOTER2 from CooksonElectronics) and a suitable reagent (e.g., di-p-xylylene ordichloro-di-p-xylylene) as the coating feed material. Parylene compoundsare commercially available, for example, from Specialty Coating Systems,Indianapolis, Ind.), including PARYLENE N(di-p-xylylene), PARYLENE C (amonchlorinated derivative of PARYLENE N, and PARYLENE D, a dichlorinatedderivative of PARYLENE N).

Paditaxel derivative/polymer with an inert-solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be immersed, either partially or completely, in a paclitaxelderivative/polymer/solvent solution for a specific period of time; Therate of immersion into the paclitaxel derivative/polymer/solventsolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thedevice can then be removed from the solution. The rate at which thedevice can be withdrawn from the solution can be altered (e.g., 0.001 cmper sec to 50 cm per sec). The coated device can be air-dried. Thedipping process can be repeated one or more times depending on thespecific application. The device can be dried under vacuum to reduceresidual solvent levels. This process will result in the paclitaxelderivative/polymer being coated on a surface of the device.

Paclitaxel/derivative/polymer with a swelling solvent

In one embodiment, the solvent is one that will not dissolve the devicebut will be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be immersed, either partially orcompletely, in a paclitaxel derivative/polymer/solvent solution for aspecific period of time (seconds to days). The rate of immersion intothe paclitaxel derivative/polymer/solvent solution can be altered (e.g.,0.001 cm per sec to 50 cm per sec). The device can then be removed fromthe solution. The rate at which the device can be withdrawn from thesolution can be altered (e.g., 0.001 cm per sec to 50 cm per sec). Thecoated device can be air-dried. The dipping process can be repeated oneor more times depending on the specific application. The device can bedried under vacuum to reduce residual solvent levels. This process willresult in the paclitaxel derivative/polymer being coated on a surface ofthe device as well as the potential for the paclitaxel derivative beingadsorbed into the medical device. The paclitaxel derivative may also bepresent on a surface of the device. The amount of surface associatedpaclitaxel derivative may be reduced by dipping the coated device into asolvent for the paclitaxel derivative or by spraying the coated devicewith a solvent for the paclitaxel derivative.

Paclitaxel derivative/polymer with a solvent

In one embodiment, the solvent is one that will be absorbed by thedevice and that will dissolve the device. The device can be immersed,either partially or completely, in a paclitaxel derivative/solventsolution for a specific period of time (seconds to hours). The rate ofimmersion into the paclitaxel derivative/solvent solution can be altered(e.g., 0.001 cm per sec to 50 cm per sec). The device can then beremoved from the solution. The rate at which the device can be withdrawnfrom the solution can be altered (e.g., 0.001 cm per sec to 50 cm persec). The coated device can be air-dried. The dipping process can berepeated one or more times depending on the specific application. Thedevice can be dried under vacuum to reduce residual solvent levels. Inthe preferred embodiment, the exposure time of the device to the solventcan be such that there are not significant permanent dimensional changesto the device (other than those associated with the coating itself). Thepaclitaxel derivative may also be present on a surface of the device.The amount of surface associated paclitaxel derivative may be reduced bydipping the coated device into a solvent for the paclitaxel derivativeor by spraying the coated device with a solvent for the paclitaxelderivative.

In the above description the device can be a device that has not beenmodified as well as a device that has been further modified by coatingwith a polymer (e.g., parylene), surface treated by plasma treatment,flame treatment, corona treatment, surface oxidation or reduction,surface etching, mechanical smoothing or roughening, or grafting priorto the coating process.

In another embodiment, a suspension of the paclitaxel derivative in apolymer solution can be prepared. The suspension can be prepared bychoosing a solvent that can dissolve the polymer but not the paclitaxelderivative or a solvent that can dissolve the polymer and in which thepaclitaxel derivative is above its solubility limit. In similarprocesses described above, a device can be dipped into the suspension ofthe fibrosis-inhibiting and polymer solution such that the device iscoated with a polymer that has a paclitaxel derivative suspended withinit.

b) Spray coating

Spray coating is another coating process that can be used. In a spraycoating process, a solution or suspension of a paclitaxel derivative,with or without a polymeric or non-polymeric carrier, is nebulized anddirected to the device to be coated by a stream of gas. One can usespray devices such as an air-brush (for example models 2020, 360, 175,100, 200, 150, 350, 250, 400, 3000, 4000, 5000, 6000 from BadgerAir-brush Company, Franklin Park, IL), spray painting equipment, TLCreagent sprayers (for example Part# 14545 and 14654, Alltech Associates,Inc. Deerfield, IL, and ultrasonic spray devices (for example thoseavailable from Sono-Tek, Milton, NY). One can also use powder sprayersand electrostatic sprayers.

In one embodiment, the paclitaxel derivative is dissolved in a solventfor the fibrosis agent and is then sprayed onto the device.

Paclitaxel derivative with an inert-solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be held in place or the device can be mounted onto a mandrel or rodthat has the ability to move in an X, Y or Z plane or a combination ofthese planes. Using one of the above described spray devices, the devicecan be spray coated such that the device is either partially orcompletely coated with the paclitaxel derivative/solvent solution. Therate of spraying of the paclitaxel derivative/solvent solution can bealtered (e.g. 0.001 ml per sec to 10 mL per sec) to ensure that a goodcoating of the paclitaxel derivative is obtained. The coated device canair-dried. The spray coating process can be repeated one or more timesdepending on the specific application. The device can be dried undervacuum to reduce residual solvent levels. This process will result inthe paclitaxel derivative being coated on a surface of the device.

Paclitaxel derivative with a swelling solvent

In one embodiment, the solvent is one that will not dissolve the devicebut will be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be spray coated, either partiallyor completely, in the paclitaxel derivative/solvent solution. The rateof spraying of the paclitaxel derivative/solvent solution can be altered(e.g., 0.001 mL per sec to 10 mL per sec) to ensure that a good coatingof the paclitaxel derivative is obtained. The coated device can beair-dried. The spray coating process can be repeated one or more timesdepending on the specific application. The device can be dried undervacuum to reduce residual solvent levels. This process will result inthe paclitaxel derivative being adsorbed into the medical device. Thepaclitaxel derivative may also be present in a surface of the device.The amount of surface associated paclitaxel derivative may be reduced bydipping the coated device into a solvent for the paclitaxel derivativeor by spraying the coated device with a solvent for the paclitaxelderivative.

Paclitaxel derivative with a solvent

In one embodiment, the solvent is one that will be absorbed by thedevice and that will dissolve the device. The device can be spraycoated, either partially or completely, in the paclitaxelderivative/solvent solution. The rate of spraying of the paclitaxelderivative/solvent solution can be altered (e.g., 0.001 mL per sec to 10mL per sec) to ensure that a good coating of the paclitaxel derivativeis obtained. The coated device can be air-dried. The spray coatingprocess can be repeated one or more times depending on the specificapplication. The device can be dried under vacuum to reduce residualsolvent levels. This process will result in the paclitaxel derivativebeing adsorbed into the medical device as well as being surfaceassociated. In the preferred embodiment, the exposure time of the deviceto the solvent can be such that there are not significant permanentdimensional changes to the device. The paclitaxel derivative may also bepresent on the surface of the device. The amount of surface associatedpaclitaxel derivative may be reduced by dipping the coated device into asolvent for the paclitaxel derivative or by spraying the coated devicewith a solvent for the paclitaxel derivative.

In the above description the device can be a device that has not beenmodified as well as a device that has been further modified by coatingwith a polymer (e.g., parylene), surface treated by plasma treatment,flame treatment, corona treatment, surface oxidation or reduction,surface etching, mechanical smoothing or roughening, or grafting priorto the coating process.

In one embodiment, the paclitaxel derivative and a polymer are dissolvedin a solvent, for both the polymer and the anti-fibrosing agent; and arethen spray coated onto the device.

Paclitaxel derivative/polymer with an inert-solvent

In one embodiment, the solvent is an inert solvent for the device suchthat the solvent does not dissolve the medical device to any greatextent and is not absorbed by the device to any great extent. The devicecan be spray coated, either partially or completely, in the paclitaxelderivative/polymer/solvent solution for a specific period of time. Therate of spraying of the paclitaxel derivative/solvent solution can bealtered (e.g., 0.001 ml per sec to 10 ml per sec) to ensure that a goodcoating of the paclitaxel derivative is obtained. The coated device canbe air-dried. The spray coating process can be repeated one or moretimes depending on the specific application. The device can be driedunder vacuum to reduce residual solvent levels. This process will resultin the paciitaxel derivative/polymer being coated on the surface of thedevice.

Paclitaxel derivative/polymer with a swelling solvent

In one embodiment, the solvent is one that will not dissolve the devicebut will be absorbed by the device. These solvents can thus swell thedevice to some extent. The device can be spray coated, either partiallyor completely, in the paclitaxel derivative/polymer/solvent solution.The rate of spraying of the paclitaxel derivative/solvent solution canbe altered (e.g., 0.001 mL per sec to 10 mL per sec) to ensure that agood coating of the paclitaxel derivative is obtained. The coated devicecan be air-dried. The spray coating process can be repeated one or moretimes depending on the specific application. The device can be driedunder vacuum to reduce residual solvent levels. This process will resultin the paclitaxel derivative/polymer being coated onto the surface ofthe device as well as the potential for the paclitaxel derivative beingadsorbed into the medical device. The paclitaxel derivative may also bepresent on the surface of the device. The amount of surface associatedpaclitaxel derivative may be reduced by dipping the coated device into asolvent for the paclitaxel derivative or by spraying the coated devicewith a solvent for the paclitaxel derivative.

Paclitaxel derivative/polymer with a solvent

In one embodiment, the solvent is one that will be absorbed by thedevice and that will dissolve the device. The device can be spraycoated, either partially or completely, in the paclitaxelderivative/solvent solution. The rate of spraying of the paclitaxelderivative/solvent solution can be altered (e.g., 0.001 mL per sec to 10mL per sec) to ensure that a good coating of the paclitaxel derivativeis obtained. The coated device can be air-dried. The spray coatingprocess can be repeated one or more times depending on the specificapplication. The device can be dried under vacuum to reduce residualsolvent levels. In the preferred embodiment, the exposure time of thedevice to the solvent can be such that there are not significantpermanent dimensional changes to the device (other than those associatedwith the coating itself). The paclitaxel derivative may also be presenton the surface of the device. The amount of surface associatedpaclitaxel derivative may be reduced by dipping the coated device into asolvent for the Paclitaxel derivative or by spraying the coated devicewith a solvent for the paclitaxel derivative.

In the above description the device can be a device that has not beenmodified as well as a device that has been further modified by coating(entirely or partially) with a polymer (e.g., parylene), surface treatedby plasma treatment, flame treatment, corona treatment, surfaceoxidation or reduction, surface etching, mechanical smoothing orroughening, or grafting prior to the coating process.

In another embodiment, a suspension of the paclitaxel derivative in apolymer solution can be prepared. The suspension can be prepared bychoosing a solvent that can dissolve the polymer but not the paclitaxelderivative or a solvent that can dissolve the polymer and in which thepaclitaxel derivative is above its solubility limit. In similarprocesses described above, the suspension of the fibrosis-inhibiting andpolymer solution can be sprayed onto the device such that the device iscoated with a polymer that has a paclitaxel derivative suspended withinit.

In all such embodiments, the devices may comprise one or more partial orcomplete coatings comprising a paclitaxel derivative. The devices mayalso comprise a paclitaxel derivative-free top coating.

2) Localized Delivery of Paclitaxel Derivatives to Treatment Site

In another aspect, a paclitaxel derivative may be delivered to thetreatment site via systemic, regional or local delivery methods. In oneaspect, the paclitaxel derivative or a composition comprising apaclitaxel derivative may be infiltrated into or onto tissue surroundingthe stent. The tissue cavity into which the stent is placed can betreated with a paclitaxel derivative prior to, during, or after theprocedure. Several of the techniques that can be used to achievepreferentially elevated levels of paclitaxel derivatives in the vicinityof the stent include: (a) using drug-delivery catheters for local,regional or systemic delivery of fibrosis inhibiting agents to thetissue surrounding the device or implant (typically, drug deliverycatheters are advanced through the circulation or inserted directly intotissues under radiological guidance (e.g., magnetic, ultrasonic, or MRIguidance) until they reach the desired anatomical location; the fibrosisinhibiting agent can then be released from the catheter lumen in highlocal concentrations in order to deliver therapeutic doses of the drugto the tissue surrounding the device or implant); (b) chemicalmodification of the fibrosis-inhibiting drug or formulation designed toincrease uptake of the agent into damaged tissues (e.g., antibodiesdirected against damaged or healing tissue components such asmacrophages, neutrophils, smooth muscle cells, fibroblasts,extracellular matrix components, neovascular tissue); (c) chemicalmodification of the fibrosis inhibiting drug or formulation designed tolocalize the drug to areas of bleeding or disrupted vasculature; (d)direct injection of the paclitaxel derivative into the tissue, forexample, under endoscopic vision; and/or applying the composition intothe anatomical space where the device will be placed (e.g., using asprayable formulation or a polymeric gel loaded with a paclitaxelderivative), where the composition may be applied to the implantationsite (e.g., topical application) or the implant/device surface.

Sustained-Release Preparations of Paditaxel Derivatives

As described previously desired paclitaxel derivatives may be admixedwith, blended with; conjugated to, or, otherwise modified to contain apolymer composition (which may be either biodegradable ornon-biodegradable) or a non-polymeric composition in order to releasethe therapeutic agent, and in a preferred embodiment, over a prolongedperiod of time. For many of the aforementioned embodiments, localizeddelivery as well as localized sustained delivery of the fibrosisinhibiting agent may be desired. For example, a desired paclitaxelderivative may be admixed with, blended with, conjugated to, or,otherwise modified to contain a polymeric composition (which may beeither biodegradable or non-biodegradable) or non-polymeric compositionin order to release the paclitaxel derivative over a period of time.

Numerous polymeric and non-polymeric compositions may be used in thepractice of the invention.

In one aspect, polymeric compositions may include a biodegradablepolymer. Representative examples of biodegradable polymers suitable forthe delivery of paclitaxel derivatives include albumin, collagen,gelatin, hyaluronic acid, starch, cellulose and cellulose derivatives(e.g., methylcellulose, hydroxypropylcellulose,hydroxypropylmethylcellulose, carboxymethylcellulose, cellulose acetatephthalate, cellulose acetate succinate, hydroxypropylmethylcellulosephthalate), casein, dextrans, polysaccharides, fibrinogen, poly(etherester) multiblock copolymers, based on poly(ethylene glycol) andpoly(butylene terephthalate), tyrosine-derived polycarbonates (e.g.,U.S. Pat. No. 6,120,491), poly(hydroxyl acids), poly(D,L-lactide),poly(D,L-lactide-co-glycolide), poly(glycolide), poly(hydroxybutyrate),polydioxanone, poly(alkylcarbonate) and poly(orthoesters), polyesters,poly(hydroxyvaleric acid), polydioxanone, degradable polyesters,poly(malic acid), poly(tartronic acid), poly(acrylamides),polyanhydrides, polyphosphazenes, poly(amino acids), poly(alkyleneoxide)-poly(ester) block copolymers (e.g., X—Y, X—Y—X or Y—X—Y,R—(Y—X)_(n), R—(X—Y)_(n) where X is a polyalkylene oxide and Y is apolyester (e.g., polyester can comprise the residues of one or more ofthe monomers selected from lactide, lactic acid, glycolide, glycolicacid, ε-caprolactone, gamma-caprolactone, hydroxyvaleric acid,hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone,gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylenecarbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one.), R is amultifunctional initiator and copolymers as well as blends thereof) andthe copolymers as well as blends thereof (see generally, Illum. L.,Davids, S.S. (eds) “Polymers in Controlled Drug Delivery” Wright,Bristol, 1987; Arshady, J. Controlled Release 17:1-22, 1991; Pitt, Int.J. Phar. 59:173-196, 1990; Holland et al., J. Controlled Release 4:155-0180, 1986).

In another aspect, polymeric compositions may include anon-biodegradable polymer. Representative examples of non-degradablepolymers suitable for the delivery of paclitaxel derivatives includepoly(ethylene-co-vinyl acetate) (“EVA”) copolymers, non-degradablepolyesters, such as poly(ethylene terephthalate), silicone rubber,acrylic polymers (polyacrylate, polyacrylic acid, polymethylacrylicacid, polymethylmethacrylate, poly(butyl methacrylate)),poly(alkylcynoacrylate) (e.g., poly(ethylcyanoacrylate),poly(butylcyanoacrylate) poly(hexylcyanoacrylate)poly(octylcyanoacrylate)), acrylic resin, polyethylene, polypropylene,polyamides (nylon 6,6), polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEXAL, BIONATE; and PELLETHANE), poly(ester urethanes), poly(etherurethanes), poly(ester-urea), cellulose esters (e.g., nitrocellulose),polyethers (poly(ethylene oxide), poly(propylene oxide), polyoxyalkyleneether block copolymers based on ethylene oxide and propylene oxide suchas the PLURONIC polymers (e.g., F-127 or F87) from BASF Corporation(Mount Olive, N.J.), and poly(tetramethylene glycol), styrene-basedpolymers (polystyrene, poly(styrene sulfonic acid),poly(styrene)-block-poly(isobutylene)-block-poly(styrene),poly(styrene)-poly(isoprene) block copolymers), and vinyl polymers(polyvinylpyrrolidone, poly(vinyl alcohol), poly(vinyl acetatephthalate) as well as copolymers and blends thereof. Polymers may alsobe developed which are either anionic (e.g., alginate, carrageenan,carboxymethyl cellulose, poly(acrylamido-2-methyl propane sulfonic acid)and copolymers thereof, poly(methacrylic acid and copolymers thereof andpoly(acrylic acid) and copolymers thereof, as well as blends thereof, orcationic (e.g., chitosan, poly-L-lysine; polyethylenimine, andpoly(allyl amine)) and blends, copolymers and branched polymers thereof(see generally, Dunn et al., J. Applied Polymer Sci: 50:353-365, 1993;Cascone et al., J. Materials Sci.: Materials in Medicine 5:770-774,1994; Shiraishi et al., Biol. Pharm. Bull. 16(11):1164-1168, 1993;Thacharodi and Rao, Int'l J. Pharm. 120:115-118, 1995; Miyazaki et al.,Int'l J. Pharm. 118:257-263, 1995).

Examples of preferred polymeric carriers include poly(ethylene-co-vinylacetate), polyurethanes (e.g., CHRONOFLEX AR, CHRONOFLEXAL, BIONATE, andPELLETHANE), poly (D,L-lactic acid) oligomers and polymers, poly(L-lactic acid) oligomers and polymers, poly (glycolic acid), copolymersof lactic acid and glycolic acid, poly (caprolactone), poly(valerolactone), polyanhydrides; copolymers of poly (caprolactone) orpoly (lactic acid) with a polyethylene glycol (e.g., MePEG),poly(alkylene oxide)-poly(ester)block copolymers (e.g., X—Y, X—Y—X orY—X—Y, R—(Y—X)_(n), R—(X—Y)_(n) where X is a polyalkylene oxide and Y isa polyester (e.g., polyester can comprise the residues of one or more ofthe monomers selected from lactide, lactic acid, glycolide, glycolicacid, ε-caprolactone, gamma-caprolactone, hydroxyvaleric acid,hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone,gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethylenecarbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one.), R is amultifunctional initiator and copolymer as well as blends thereof),nitrocellulose, silicone rubbers,poly(styrene)block-poly(isobutylene)-block-poly(styrene), poly(acrylate)polymers and blends, admixtures, or co-polymers of any of the above.Other preferred polymers include collagen, poly(alkylene oxide)-basedpolymers, polysaccharides such as hyaluronic acid, chitosan and fucans,and copolymers of polysaccharides with degradable polymers, as well asblends thereof.

Other representative polymers capable of release (e.g., sustainedlocalized delivery) of paclitaxel derivatives include carboxylicpolymers, polyacetates, polycarbonates, polyethers, polyethylenes,polyvinylbutyrals, polysilanes, polyureas, polyoxides, polystyrenes,polysulfides, polysulfones, polysulfonides, polyvinylhalides,pyrrolidones, rubbers, thermal-setting polymers, cross-linkable acrylicand methacrylic polymers, ethylene acrylic acid copolymers, styreneacrylic copolymers, vinyl acetate polymers and copolymers, vinyl acetalpolymers and copolymers, epoxies, melamines, other amino resins,phenolic polymers, and copolymers thereof, water-insoluble celluloseester polymers (including cellulose acetate propionate, celluloseacetate, cellulose acetate butyrate, cellulose nitrate, celluloseacetate phthalate, and mixtures thereof), polyvinylpyrrolidone,polyethylene glycols, polyethylene oxide, polyvinyl alcohol, polyethers,polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, dextran,xanthan, hydroxypropyl cellulose, and homopolymers and copolymers ofN-vinylpyrrolidone, N-vinyllactam, N-vinyl butyrolactam, N-vinylcaprolactam, other vinyl compounds having polar pendant groups, acrylateand methacrylate having hydrophilic esterifying groups, hydroxyacrylate,and acrylic acid, and combinations thereof; cellulose esters and ethers,ethyl cellulose, hydroxyethyl cellulose, cellulose nitrate, celluloseacetate, cellulose acetate butyrate, cellulose acetate propionate,natural and synthetic elastomers, rubber, acetal, styrene polybutadiene,acrylic resin, polyvinylidene chloride, polycarbonate, homopolymers andcopolymers of vinyl compounds, polyvinylchloride, and polyvinylchlorideacetate.

Representative examples of patents relating to drug-delivery polymersand the preparation included PCT Publication Nos. WO 98/19713, WO01/17575, WO 01/41821; WO 01/41822, and WO 01/15526 (as well as thecorresponding U.S. applications); U.S. Pat Nos. 4,500,676, 4,582,865,4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743, 5,069,899,5,099,013, 5,128,326, 5,143,724, 5,153,174, 5,246,698, 5,266,563,5,399,351, 5,525,348, 5,800,412, 5,837,226, 5,942,555, 5,997,517,6,007,833, 6,071,447, 6,090,995, 6,106,473, 6,110,483, 6,121,027,6,156,345, 6,214,901, 6,368,611, 6,630,155, 6,528,080, RE37,950,6,46,1631, 6,143,314, 5,990,194, 5,792,469, 5,780,044, 5,759,563,5,744,153, 5,739,176, 5,733,950, 5,681,873, 5,599,552, 5,340,849,5,278,202, 5,278,201, 6,589,549, 6,287,588, 6,201,072, 6,117,949,6,004,573, 5,702,717, 6,413,539, 5,714,159, 5,612,052; and U.S. PatentApplication Publication Nos. 2003/0068377, 2002/0192286, 2002/0076441,and 2002/0090398.

In one embodiment, all or a portion of the device is coated with aprimer (bonding) layer and a drug release layer, as described in U.S.Patent application entitled, “Stent with Medicated Multi-Layer HybridPolymer Coating,” filed Sep. 16, 2003 (U.S. Ser. No. 10/662,877).

In order to develop a hybrid polymer delivery system for targetedtherapy, it is desirable to be able to control and manipulate theproperties of the system both in terms of physical and drug releasecharacteristics. The active agents can be imbibed into a surface hybridpolymer layer, or incorporated directly into the hybrid polymer coatingsolutions. Imbibing drugs into surface polymer layers is an efficientmethod for evaluating polymer-drug performance in the laboratory, butfor commercial production it may be preferred for the polymer and drugto be premixed in the casting mixture. Greater efficacy can be achievedby combining the two elements in the coating compostions in order tocontrol the ratio of active agent to polymer in the coatings. Suchratios are important parameters to the final properties of the medicatedlayers, i.e., they allow for better control of active agentconcentration and duration of pharmacological activity.

Typical polymers used in the drug-release system can includewater-insoluble cellulose esters, various polyurethane polymersincluding hydrophilic and hydrophobic versions, hydrophilic polymerssuch as polyethylene glycol (PEG), polyethylene oxide (PEO),polyvinylpyrrolidone (PVP), PVP copolymers such as vinyl acetate,hydroxyethyl methacrylate (HEMA) and copolymers such asmethylmethacrylate (PMMA-HEMA), and other hydrophilic and hydrophobicacrylate polymers and copolymers containing functional groups such ascarboxyl and/or hydroxyl.

Cellulose esters such as cellulose acetate, cellulose acetatepropionate, cellulose acetate butyrate, cellulose acetate phthalate, andcellulose nitrate may be used. In one aspect of the invention, thetherapeutic agent is formulated with a cellulose ester. Cellulosenitrate is a preferred cellulose ester because of its compatibility withthe active agents and its ability to impart non-tackiness andcohesiveness to the coatings. Cellulose nitrate has been shown tostabilize entrapped drugs in ambient and processing conditions. Variousgrades of cellulose nitrate are available and may be used in a coatingon a device, including cellulose nitrate having a nitrogencontent=11.8-12.2%. Various viscosity grades, including 3.5, 0.5 or 0.25seconds, may be used in order to provide proper rheological propertieswhen combined with the coating solids used in these formulations. Higheror lower viscosity grades can be used. However, the higher viscositygrades can be more difficult to use because of their higher viscosities.Thus, the lower viscosity grades, such as 3.5, 0.5 or 0.25 seconds, aregenerally preferred. Physical properties such as tensile strength,elongation, flexibility, and softening point are related to viscosity(molecular weight) and can decrease with the lower molecular weightspecies, especially below the 0.25 second grades.

The cellulose derivatives comprise hydroglucose structures. Cellulosenitrate is a hydrophobic, water-insoluble polymer, and has high waterresistance properties. This structure leads to high compatibility withmany active agents, accounting for the high degree of stabilizationprovided to drugs entrapped in cellulose nitrate. The structure ofnitrocellulose is given below:

Cellulose nitrate is a hard, relatively inflexible polymer, and haslimited adhesion to many polymers that are typically used to makemedical devices. Also control of drug elution dynamics is limited ifonly one polymer is used in the binding matrix. Accordingly, in oneembodiment of the invention, the therapeutic agent is formulated withtwo or more polymers before being associated with the device. In oneaspect, the agent is formulated with the both polyurethane ((e.g.,CHRONOFLEX AR, CHRONOFLEX AL, and BIONATE, PELLETHANE) and cellulosenitrate to provide a hybrid polymer drug loaded matrix. Polyurethanesprovide the hybrid polymer matrix with greater flexibility and adhesionto the device, particularly when the device has been pre-coated with aprimer. Polyurethanes can also be used to slow or hasten the drugelution from coatings. Aliphatic, aromatic, polytetramethylene etherglycol, and polycarbonate are among the types of polyurethanes, whichcan be used in the coatings. In one aspect, a paclitaxel derivative(e.g., paclitaxel) may be incorporated into a carrier that includes apolyurethane and a cellulose derivative. A heparin complex, such asbenzalkonium heparinate or tridodecylammonium heparinate), mayoptionally be included in the formulation.

From the structure below, it is possible to see how more or lesshydrophilic polyurethane polymers may be created based on the number ofhydrophilic groups contained in the polymer structures. In one aspect ofthe invention, the device is associated with a formulation that includestherapeutic agent, cellulose ester, and a polyurethane that iswater-insoluble, flexible, and compatible with the cellulose ester.

Polyvinylpyrrolidone (PVP) is a polyamide that possesses unusualcomplexing and colloidal properties and is essentially physiologicallyinert. PVP and other hydrophilic polymers are typically biocompatible.PVP may be incorporated into drug loaded hybrid polymer compositions inorder to increase drug release rates. In one embodiment, theconcentration of PVP that is used in drug loaded hybrid polymercompositions can be less than 20%. This concentration cannot make thelayers bioerodable or lubricious. In general, PVP concentrations from<1% to greater than 80% are deemed workable. In one aspect of theinvention, the therapeutic agent that is associated with an device isformulated with a PVP polymer.

Acrylate polymers and copolymers including polymethylmethacrylate (PMMA)and polymethylmethacrylate hydroxyethyl methacrylate (PMMA/HEMA) areknown for their biocompatibility as a result of their widespread use incontact and intraocular lens applications. This class of polymergenerally provokes very little smooth muscle and endothelial cellgrowth, and very low inflammatory response (Bar). Thesepolymers/copolymers are compatible with drugs and the other polymers andlayers of the instant invention. Thus, in one aspect, the device isassociated with a composition that comprises a paclitaxel derivative asdescribed above, and an acrylate polymer or copolymer.

Methylmethacrylate hydroxyethylmethacrylate copolymer

It should be obvious to one of skill in the art that the polymers asdescribed herein can also be blended or copolymerized in variouscompositions as required to deliver therapeutic doses of paclitaxelderivatives.

Polymeric carriers for paclitaxel derivatives can be fashioned in avariety of forms, with desired release characteristics and/or withspecific properties depending upon the device, composition or implantbeing utilized. For example, polymeric carriers may be fashioned torelease a paclitaxel derivative upon exposure to a specific triggeringevent such as pH (see, e.g., Heller et al., “Chemically Self-RegulatedDrug Delivery Systems,” in Polymers in Medicine III, Elsevier SciencePublishers B.V., Amsterdam, 1988, pp. 175-188; Kang et al., J. AppliedPolymer Sci. 48:343-354, 1993; Dong et al., J. Controlled Release19:171-178, 1992; Dong and Hoffman, J. Controlled Release 15:141-152,1991; Kim et al., J. Controlled Release 28:143-152, 1994; Cornejo-Bravoet al., J. Controlled Release 33:223-229, 1995; Wu and Lee, Pharm. Res.10(10):1544-1547, 1993; Serres et al., Pharm. Res: 13(2):196-201, 1996;Peppas, “Fundamentals of pH- and Temperature-Sensitive DeliverySystems,” in Gurny et al. (eds.), Pulsatile Drug Delivery,Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55;Doelker, “Cellulose Derivatives,” 1993, in Peppas and Langer (eds.),Bipolymers I, Springer-Verlag, Berlin). Representative examples ofpH-sensitive polymers include poly (acrylic acid) and its derivatives(including for example, homopolymers such as poly(aminocarboxylic acid);poly(acrylic acid); poly(methyl acrylic acid), copolymers of suchhomopolymers, and copolymers of poly(acrylic acid) and/or acrylate oracrylamide lmonomers such as those discussed above. Other pH sensitivepolymers include polysaccharides such as cellulose acetate phthalate;hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcelluloseacetate succinate; cellulose acetate trimellilate; and chitosan. Yetother pH sensitive polymers include any mixture of a pH sensitivepolymer and a water-soluble polymer.

Likewise, paclitaxel derivatives can be delivered via polymeric carrierswhich are temperature sensitive (see, e.g., Chen et al., “NovelHydrogels of a Temperature-Sensitive PLURONIC Grafted to a BioadhesivePolyacrylic Acid Backbone for Vaginal Drug Delivery,” in Proceed.Intern. Symp. Control. Rel. Bioact. Mater. 22:167-168, ControlledRelease Society, Inc., 1995; Okano, “Molecular Design ofStimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery,” inProceed. Intern. Symp. Control. Rel. Bioact. Mater: 22:111-112,Controlled Release Society, Inc., 1995; Johnston et al., Pharm. Res.9(3):425-433, 1992; Tung, Int'l J. Pharm. 107:8590, 1994; Harsh andGehrke, J. Controlled Release 17:175-186, 1991; Bae et al., Pharm. Res.8(4):531-537, 1991; Dinarvand and D'Emanuele, J. Controlled Release36:221-227, 1995; Yu and Grainger, “Novel Thermo-sensitive AmphiphilicGels: Poly N-isopropylacrylamide-co-sodiumacrylate-co-n-N-alkylacrylamide Network Synthesis and PhysicochemicalCharacterization,” Dept. of Chemical & Biological Sci., Oregon GraduateInstitute of Science & Technology, Beaverton, Oreg., pp. 820-821; Zhouand Smid, “Physical Hydrogels of Associative Star Polymers,” PolymerResearch Institute, Dept. of Chemistry, College of Environmental Scienceand Forestry, State Univ. of New York, Syracuse, N.Y., pp. 822-823;Hoffman et al., “Characterizing Pore Sizes and Water ‘Structure’ inStimuli-Responsive Hydrogels,” Center for Bioengineering, Univ. ofWashington, Seattle, Wash., p. 828; Yu and Grainger, “Thermo-sensitiveSwelling Behavior in Crosslinked N-isopropylacrylamide Networks:Cationic, Anionic and Ampholytic Hydrogels,” Dept. of Chemical &Biological Sci., Oregon Graduate Institute of Science & Technology,Beaverton, Oreg., pp. 829-830; Kim et al., Pharm. Res. 9(3):283-290,1992; Bae et al., Pharm. Res. 8(5):624-628, 1991; Kono et al., J.Controlled Release 30:69-75, 1994; Yoshida et al., J. Controlled Release32:97-102, 1994; Okano et al., J. Controlled Release 36:125-133, 1995;Chun and Kim, J. Controlled Release 38:39-47, 1996; D'Emanuele andDinarvand, Int'l J. Pharm. 118:237-242, 1995; Katono et al., J.Controlled Release 16:215-228, 1991; Hoffman, “Thermally ReversibleHydrogels Containing Biologically Active Species,” in Migliaresi et al.(eds.), Polymers in Medicine III, Elsevier Science Publishers B.V.,Amsterdam, 1988, pp. 161-167; Hoffman, “Applications of ThermallyReversible Polymers and Hydrogels in Therapeutics and Diagnostics,” inThird International Symposium on Recent Advances in Drug DeliverySystems, Salt Lake City; UT, Feb. 24-27, 1987, pp. 297-305; Gutowska etal., J. Controlled Release 22:95-104, 1992; Palasis and Gehrke, J.Controlled Release 18:1-12, 1992; Paavola et al., Pharm. Res. 12(12):1997-2002, 1995).

Representative examples of thermogelling polymers, and the gelatintemperature (LCST (° C.)) include homopolymers such aspoly(N-methyl-N-n-propylacrylamide), 19.8° C.;poly(N-n-propylacrylamide), 21.5° C.;poly(N-methyl-N-isopropylacrylamide), 22.3° C.;poly(N-n-propylmethacrylamide), 28.0° C.; poly(N-isopropylacrylamide),30.9° C.; poly(N, n-diethylacrylamide), 32.0° C.;poly(N-isopropylmethacrylamide), 44.0° C.;poly(N-cyclopropylacrylamide), 45.5° C.; poly(N-ethylmethyacrylamide),50.0° C.; poly(N-methyl-N-ethylacrylamide), 56.0° C.;poly(N-cyclopropylmethacrylamide), 59.0° C.; poly(N-ethylacrylamide),72.0° C. Moreover thermogelling polymers may be made by preparingcopolymers between (among) monomers of the above, or by combining suchhomopolymers with other water-soluble polymers such as acrylmonomers(e.g., acrylic acid and derivatives thereof, such as methylacrylic acid,acrylate monomers and derivatives thereof, such as butyl methacrylate,butyl acrylate, lauryl acrylate, and acrylamide monomers and derivativesthereof, such as N-butyl acrylamide and acrylamide).

Other representative examples of thermogelling polymers includecellulose ether derivatives such as hydroxypropyl cellulose, 41° C.;methyl cellulose, 55° C.; hydroxypropylmethyl cellulose, 66° C.; andethylhydroxyethyl cellulose, polyalkylene oxide-polyester blockcopolymers of the structure X—Y, Y—X—Y and X—Y—X where X in apolyalkylene oxide and Y is a biodegradable polyester (e.g.,PLG-PEG-PLG) and PLURONICs such as F-127, 10° C.- 15° C.; L-122, 19° C.;L-92, 26° C.; L-81, 20° C.; and L-61, 24° C.

Representative examples of patents relating to thermally gellingpolymers and the preparation include U.S. Pat. Nos; 6,451,346;6,201,072; 6,117,949; 6,004,513; 5,702;717; and 5,484,610; and PCTPublication Nos. WO 99/07343; WO 99/18142; WO 03/17972; WO 01/82970; WO00/18821; WO 97/15287; WO 01/41735; WO 00/00222 and WO 00/38651.

Paclitaxel derivatives may be linked by occlusion in the matrices of thepolymer, bound by covalent linkages, or encapsulated in microcapsules.Within certain imbodiments of the invention, therapeutic compositionsare provided in non-capsular formulations such as microspheres (rangingfrom nanometers to micrometers in size), pastes, threads of varioussize, films, or sprays. In one aspect, the paclitaxel derivative may beincorporated into biodegradable magnetic nanospheres. The nanospheresmay be used, for example, to replenish a paclitaxel derivative into animplanted intravascular device, such as a stent containing a weakmagnetic alloy (see, e.g., Z. Forbes, B.B. Yellen, G. Friedman, K.Barbee. “An approach to targeted drug delivery based on uniform magneticfields,” IEEE Trans. Magn. 39(5): 3372-3377 (2003)).

Within certain aspects of the present invention, therapeuticcompositions may be fashioned in the form of microspheres,microparticles and/or nanoparticles having any size ranging from about30 nm to 500 μm, depending upon the particular use. These compositionscan be formed by spray-drying methods, milling methods, coacervationmethods, W/O emulsion methods, W/O/W emulsion methods, and solventevaporation methods. In other aspects, these compositions can includemicroemulsions, emulsions, liposomes and micelles. Alternatively, suchcompositions may also be readily applied as a “spray”, which solidifiesinto a film or coating for use as a device/implant surface coating or toline the tissues of the implantation site. Such, sprays may be preparedfrom microspheres of a wide array of sizes, including for example, from0.1 μm to 3 μm, from 10 μm to 30 μm, and from 30 μm to 100 μm.

Therapeutic compositions of the present invention may also be preparedin a variety of “paste” or gel forms. For example, within one embodimentof the invention, therapeutic compositions are provided which are liquidat one temperature (e.g., temperature greater than 37° C., such as 40°C., 45° C., 50° C., 55° C. or 60° C.), and solid or semi-solid atanother temperature (e.g., ambient body temperature, or any temperaturelower than 37° C.). Such “thermopastes” maybe readily made utilizing avariety of techniques (see, e.g., PCT Publication WO 98/24427). Otherpastes may be applied as a liquid, which solidify in vivo due todissolution of a water-soluble component of the paste and precipitationof encapsulated drug into the aqueous body environment. These “pastes”and “gels” containing paclitaxel derivatives are particularly useful forapplication to the surface of tissues that will be in contact with theimplant or device.

Within yet other aspects of the invention, the therapeutic compositionsof the present invention may be formed as a film or tube. These films ortubes can be porous or non-porous. Preferably, such films or tubes aregenerally less than 5, 4, 3, 2, or 1 mm thick, more preferably less than0.75 mm, 0.5 mm, 0.25 mm, or, 0.10 mm thick. Films or tubes can also begenerated of thicknesses less than 50 μm, 25 μm or 10 μm. Such films arepreferably flexible with a good tensile strength (e.g., greater than 50,preferably greater than 100, and more preferably greater than 150 or 200N/cm²), good adhesive properties (i.e., adheres to moist or wetsurfaces), and have controlled permeability. Paclitaxel derivativescontained in polymeric films are particularly useful for application tothe surface of a stent as well as to the surface of tissue.

Within further aspects of the present invention, polymeric carriers areprovided which are adapted to contain and release a hydrophobicfibrosis-inhibiting compound, and/or the carrier containing thehydrophobic compound in combination with a carbohydrate, protein orpolypeptide. Within certain embodiments, the polymeric carrier containsor comprises regions, pockets, or granules of one or more hydrophobiccompounds. For example, within one embodiment of the invention,hydrophobic compounds may be incorporated within a matrix which containsthe hydrophobic fibrosis-inhibiting compound, following by incorporationof the matrix within the polymeric carrier. A variety of matrices can beutilized in this regard, including for example, carbohydrates andpolysaccharides such as starch, cellulose, dextran, methylcellulose,sodium alginate, heparin, chitosan and hyaluronic acid, proteins orpolypeptides such as albumin, collagen and gelatin. Within alternativeembodiments, hydrophobic compounds may be contained within a hydrophobiccore, and this core contained within a hydrophilic shell.

Other carriers that may likewise be utilized to contain and deliverfibrosis-inhibiting paclitaxel derivatives described herein include:hydroxypropyl cyclodextrin (Cserhati and Hollo, Int. J. Pharm.108:69-75, 1994), liposomes (see, e.g., Sharma et al., Cancer Res. 53:5877-5881, 1993; Sharma and Straubinger, Pharm. Res. 11 (60):889-896,1994; WO 93/18751; U.S. Pat. No. 5,242,073), liposome/gel (WO 94/26254),nanocapsules (Bartoli et al., J. Microencapsulation 7(2):191-197, 1990),micelles (Alkan-Onyuksel et al., Pharm. Res. 11(2):206-212, 1994);implants (Jampel et al., Invest. Ophthalm. Vis. Science34(11):3076-3083, 1993; Walter et al., Cancer Res. 54:22017-2212, 1994),nanoparticles (Violante and Lanzafame PAACR), nanoparticles—modified(U.S. Pat. No. 5,145,684), nanoparticles (surface modified) (U.S. Pat.No. 5,399,363), micelle (surfactant) (U.S. Pat. No. 5,403,858),synthetic phospholipid compounds (U.S. Pat. No. 4,534,899), gas bornedispersion (U.S. Pat. No. 5,301,664), liquid emulsions, foam, spray,gel, lotion, cream, ointment, dispersed vesicles, particles or dropletssolid- or liquid- aerosols, microemulsions (U.S. Pat. No. 5,330,756),polymeric shell (nano- and micro- capsule) (U.S. Pat. No. 5,439,686),emulsion (Tarr et al., Pharm Res. 4:62-165, 1987), nanospheres (Hagan etal., Proc. Intern. Symp. Control Rel. Bioact. Mater. 22, 1995; Kwon etal., Pharm Res. 12(2):192-195; Kwon et al., Pharm Res. 10(7):970-974;Yokoyama et al., J. Contr. Rel. 32:269-277, 1994; Gref et al., Science263:1600-1603, 1994; Bazile et al., J. Pharm. Sci. 84:493-498, 1994) andimplants (U.S. Pat. No. 4,882,168).

Within another aspect of the present invention, polymeric carriers canbe materials that are formed in situ. In one embodiment, the precursorscan be monomers or macromers that contain unsaturated groups that can bepolymerized and/or crosslinkeds. The monomers or macromers can then, forexample, be injected into the treatment area or onto the surface of thetreatment area and polymerized in situ using a radiation source (e.g.,visible or UV light) or a free radical system (e.g., potassiumpersulfate and ascorbic acid or iron and hydrogen peroxide). Thepolymerization step can be performed immediately prior to,simultaneously to or post injection of the reagents into the treatmentsite. Representative examples of compositions that undergo free radicalpolymerization reactions are described in WO 01/44307, WO 01/68720, WO02/072166, WO 03/043552, WO 93/17669, WO 00/64977; U.S. Pat. Nos.5,900,245, 6,051,248, 6,083,524, 6,177,095, 6,201,065, 6,217,894,6,639,014, 6,352,710, 6,410,645, 6,531,147, 5,567,435, 5,986,043,6,602,975; U.S. patent application Publication Nos. 2002/012796A1,2002/0127266A1, 2002/0151650A1, 2003/0104032A1, 2002/0091229A1, and2003/0059906A1.

In another embodiment, the reagents can undergo anelectrophilic-nucleophilic reaction to produce a crosslinked matrix. Forexample, a 4-armed thiol derivatized polyethylene glycol can be reactedwith a 4 armed NHS-derivatized polyethylene glycol under basicconditions (pH>about 8). Representative examples of compositions thatundergo electrophilic-nucleophilic crosslinking reactions are describedin U.S. Pat. Nos: 5,752,974; 5,807,581; 5,874,500; 5,936,035; 6,051,648;6,165,489; 6,312,725; 6,458,889; 6,495,127; 6,534,591; 6,624,245;6,566,406; 6,610,033; 6,632,457; PCT Application Published Nos. WO04/060405 and WO 04/060346. Other examples of in situ forming materialsthat can be used include those based on the crosslinking of proteins(described in U.S. Pat. Nos. RE38158; 4,839,345; 5,514,379, 5,583,114;6,458,147; 6,371,975; U.S. Publication Nos. 2002/0161399; 2001/0018598and PCT Publication Nos: WO 03/090683; WO 01/45761; WO 99/66964 and WO96/03159).

Other examples of compositions and methods for applying (e.g., coating)these compositions to medical devices are described in U.S. Pat. Nos:6,610,016; 6,358,557; 6,306,176; 6,110,483; 6,106,473; 5,997,517;5,800,412; 5,525,348; 5,331,027; 5,001,009; 6,562,136; 6,406,754;6,344,035; 6,254,921; 6,214,901; 6,077,698; 6,603,040; 6,278,018;6,238,799; 6,096;726, 5,766,158; 5,599,576, 4,119,094; 4,100,309;6;599,558; 6,369,168; 6,521,283; 6,497,916; 6,251,964; 6,225,431;6,087,462; 6,083,257; 5,739,237; 5,739,236; 5,705,583; 5,648,442;5,645,883; 5,556,710; 5,496,581; 4,689,386; 6,214,115; 6,090,901;6,599,448; 6,054,504; 4,987,182; 4,847,324; and 4,642,267; U.S. patentapplication Publication Nos. 2002/0146581, 2003/0129130, 2003/0129130,2001/0026834; 2003/0190420; 2001/0000785; 2003/0059631; 2003/0190405;2002/0146581; 2003/020399; 2001/0026834; 2003/0190420; 2001/0000785;2003/0059631; 2003/0190405; and 2003/020399; and PCT Publication Nos. WO02/055121; WO 01/57048; WO 01/52915; and WO 01/01957.

Within another aspect of the invention, the paclitaxel derivative can bedelivered with a non-polymeric agent. These non-polymeric carriers caninclude sucrose derivatives (e.g., sucrose acetate isobutyrate, sucroseoleate), sterols such as cholesterol, stigmasterol, β-sitosterol, andestradiol; cholesteryl esters such as cholesteryl stearate; C₁₂-C₂₄fatty acids such as lauric acid, myristic acid, palmitic acid, stearicacid, arachidic acid, behenic acid, and lignoceric acid; C₁₈-C₃₆ mono-,di-and triacylglycerides such as glyceryl monooleate, glycerylmonolinoleate, glyceryl monolaurate; glyceryl monodocosanoate, glycerylmonomyristate, glyceryl monodicenoate, glyceryl dipalmitate, glyceryldidocosanoate, glyceryl dimyristate, glyceryl didecenoate, glyceryltridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glyceroltristearate and mixtures thereof; sucrose fatty acid esters such assucrose distearate and sucrose palmitate; sorbitan fatty acid esterssuch as sorbitan monostearate, sorbitan monopalmitate and sorbitantristearate; C₁₆-C₁₈ fatty alcohols such as cetyl alcohol, myristylalcohol, stearyl alcohol, and cetostearyl alcohol; esters of fattyalcohols and fatty acids such as cetyl palmitate and cetearyl palmitate;anhydrides of fatty acids such as stearic anhydride; phospholipidsincluding phosphatidylcholine (lecithin), phosphatidylserine,phosphatidylethanolamine, phosphatidylinositol, and lysoderivativesthereof; sphingosine and derivatives thereof; spingomyelins such asstearyl, palmitoyl, and tricosanyl spingomyelins; ceramides such asstearyl and palmitoyl ceramides; glycosphingolipids; lanolin and lanolinalcohols, calcium phosphate, sintered and unscintered hydoxyapatite,zeolites; and combinations and mixtures thereof.

Representative examples of patents relating to non-polymeric deliverysystems and the preparation include U.S. Pat. Nos. 5,736,152; 5,888,533;6,120,789; 5,968,542; and 5,747,058.

The paclitaxel derivative may be delivered as a solution. The paclitaxelderivative can be incorporated directly into the solution to provide ahomogeneous solution or dispersion. In certain embodiments, the solutionis an aqueous solution. The aqueous solution may further include buffersalts, as well as viscosity modifying agents (e.g., hyaluronic acid,alginates, carboxymethylcelluloe (CMC), and the like). In another aspectof the invention, the solution can include a biocompatible solvent suchas ethanol, DMSO, glycerol, PEG-200; PEG-300 or NMP.

Within another aspect of the invention, the paclitaxel derivative canfurther comprise a secondary carrier. The secondary carrier can be inthe form of microspheres (e.g., PLGA, PLLA, PDLLA, PCL, gelatin,polydioxanone, poly(alkylcyanoacrylate)), nanospheres (PLGA, PLLA,PDLLA, PCL, gelatin, polydioxanone, poly(alkylcyanoacrylate)),liposomes, emulsions, microemulsions, micelles (SDS, block copolymers ofthe form X—Y, X—Y—X or Y—X—Y, R—(Y—X)_(n), R—(X—Y)_(n) where X is apolyalkylene oxide (e.g., poly(ethylene oxide, poly(propylene oxide,block copolymers of poly(ethylene oxide) and poly(propylene oxide) and Yis a polyester (e.g., polyester can comprise the residues of one or moreof the monomers selected from lactide, lactic acid, glycolide, glycolicacid, ε-caprolactone, gamma-caprolactone, hydroxyvaleric acid,hydroxybutyric acid, beta-butyrolactone, gamma-butyrolactone,gamma-valerolactone, γ-decanolactone, δ-decanolactone, trimethlenecarbonate, 1,4-dioxane-2-one or 1,5-dioxepan-2one). R is amultifunctional initiator and copolymers as well as blends thereof.),zeolites or cyclodextrins.

Within another aspect of the invention, these paclitaxelderivative/secondary carrier compositions can be a) incorporateddirectly into or onto the device, b) incorporated into a solution, c)incorporated into a gel or viscous solution, d) incorporated into thecomposition used for coating the device or e) incorporated into or ontothe device following coating of the device with a coating composition.

For example, paclitaxel derivative loaded PLGA microspheres can beincorporated into a polyurethane coating solution which is then coatedonto the device.

In yet another example, the device can be coated with a polyurethane andthen allowed to partially dry such that the surface is still tacky. Aparticulate form of the paclitaxel derivative or paclitaxelderivative/secondary carrier can be applied to all or a portion of thetacky coating after which the device is dried.

In yet another example, the device can be coated with one of thecoatings described above. A thermal treatment process can then be usedto soften the coating, after which the paclitaxel derivative or thepaclitaxel derivative/secondary carrier is applied to the entire deviceor to a portion of the device (e.g., outer surface)

Within another aspect of the invention, the coated device which inhibitsor reduces an in vivo fibrotic reaction is further coated with acompound or compositions which delay the release of and/or activity ofthe paclitaxel derivative. Representative examples of such agentsinclude biologically inert materials such as gelatin, PLGA/MePEG film,PLA, polyurethanes, silicone rubbers, surfactants, lipids, orpolyethylene glycol, as well as biologically active materials such asheparin (e.g., to induce coagulation).

For example, in one embodiment of the invention, the active agent on thedevice is top-coated with a physical barrier. Such barriers can includenon-degradable materials or biodegradable materials such as gelatin,PLGA/MePEG film, PLA, or polyethylene glycol among others. In oneembodiment, the rate of diffusion of the therapeutic agent in barriercoat is slower that the rate of diffusion of the therapeutic agent inthe layer. In the case of PLGA/MePEG, once the PLGA/Me PEG becomesexposed to the bloodstream, the MePEG can dissolve out of the PLGA,leaving channels through the PLGA layer to an underlying layercontaining the paclitaxel derivative, which then can then diffuse intothe vessel wall and initiate its biological activity.

In another embodiment of the invention, a particulate form of the activeagent may be coated onto the stent (or any of the devices describedbelow) using a polymer (e.g., PLG, PLA, or a polyurethane). A secondpolymer, that dissolves slowly or degrades (e.g., MePEG-PLGA or PLG) andthat does not contain the active agent, may be coated over the firstlayer. Once the top layer dissolves or degrades, it exposes the undercoating which allows the active agent to be exposed to the treatmentsite or to be released from the coating.

Within another aspect of the invention, the outer layer of the coatingof a coated device, which inhibits an in vivo fibrotic response, isfurther treated to crosslink the outer layer of the coating. This can beaccomplished by subjecting the coated device to a plasma treatmentprocess. The degree of crosslinking and nature of the surfacemodification can be altered by changing the RF power setting, thelocation with respect to the plasma, the duration of treatment as wellas the gas composition introduced into the plasma chamber.

Protection of a biologically active surface can also be utilized bycoating the device surface with an inert molecule that prevents accessto the active site through steric hindrance, or by coating the surfacewith an inactive form of the paclitaxel derivative, which is lateractivated. For example, the device can be coated with an enzyme, whichcauses either release of the paclitaxel derivative or activates thepaclitaxel derivative.

In another embodiment, the device is coated with a paclitaxel derivativeand then further coated with a composition that comprises ananticoagulant such as heparin. As the antlcoagulant dissolves away, theanticoagulant activity slows or stops, and the newly exposed paclitaxelderivative is available to inhibit or reduce fibrosis from occurring inthe adjacent tissue.

The device can be coated with an inactive form of the paclitaxelderivative, which is then activated once the device is deployed. Suchactivation can be achieved by injecting another material into thetreatment area after the device (as described below) is deployed orafter the paclitaxel derivative has been administered to the treatmentarea (via, e.g., injections, spray, wash, drug delivery catheters orballoons). For example, the device can be coated with an inactive formof the paclitaxel derivative. Once the device is deployed, theactivating substance is injected or applied into or onto the treatmentsite where the inactive form of the paclitaxel derivative has beenapplied. For example, a device can be coated with a biologically activepaclitaxel derivative and a first substance having moieties that capableof forming an ester bond with another material. The coating can becovered with a second substance such as polyethylene glycol. The firstand second substances can react to form an ester bond via, e.g., acondensation reaction. Prior to the deployment of the device, anesterase is injected into the treatment site around the outside of thedevice, which can cleave the bond between the ester and the paclitaxelderivative, allowing the agent to initiate fibrosis-inhibition.

In another aspect, a medical device may include a plurality ofreservoirs within its structure, each reservoir configured to house andprotect a therapeutic drug. The reservoirs may be formed from divets inthe device surface or micropores or channels in the device body. In oneaspect, the reservoirs are formed from voids in the structure of thedevice. The reservoirs may be coated with a single type of drug or morethan one type of drug. The drug(s) may be formulated with a carrier(e.g., a polymeric or non-polymeric material) that is coated on thereservoirs. The coated reservoir can function as a drug delivery depotwhich can release drug over a period of time dependent on the releasekinetics of the drug from the carrier. In certain embodiments, thereservoir may be coated with a plurality of layers. Each layer mayinclude a different drug having a particular amount (dose) of drug, andeach layer may have a different composition to further tailor the amountof drug that is released from the substrate. The multi-layered carriermay further include a barrier layer that prevents release of thedrug(s). The barrier layer can be used, for example, to control thedirection that the drug elutes from the void. In a preferred embodiment,this drug-coated medical device may further comprise a paclitaxelderivative in one or more reservoirs.

Within certain embodiments of the invention, the therapeuticcompositions may also comprise additional ingredients such assurfactants (e.g., PLURONICS, such as F-127, L-122, L-101, L-92, L-81,and L-61), anti-inflammatory agents (e.g., dexamethasone or aspirin),anti-thrombotic agents (e.g., heparin, high activity heparin, heparinquaternary amine complexes (e.g., heparin benzalkonium chloridecomplex)), anti-infective agents (e.g., 5-fluorouracil, triclosan,rifamycim, and silver compounds), preservatives, anti-oxidants and/ oranti-platelet agents.

Within certain embodiments of the invention, the therapeutic agent orcarrier can also comprise radio-opaque, echogenic materials and magneticresonance imaging (MRI) responsive materials (i.e., MRI contrast agents)to aid in visualization of the device under ultrasound, fluoroscopyand/or MRI. For example, a device may be made with or coated with acomposition which is echogenic or radiopaque (e.g., made with echogenicor radiopaque with materials such as powdered tantalum, tungsten, bariumcarbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol,iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxilan,iodixanol, iotrolan, acetrizoic acid derivatives, diatrizoic acidderivatives, iothalamic acid derivatives, ioxithalamic acid derivatives,metrizoic acid derivatives, iodamide, lypophylic agents, iodipamide andioglycamic acid or, by the addition of microspheres or bubbles whichpresent an acoustic interface). Visualization of a device by ultrasonicimaging may be achieved using an echogenic coating. Echogenic coatingsare described in, e.g., U.S. Pat. Nos. 6,106,473 and 6,610,016. Forvisualization under MRI, contrast agents (e.g., gadolinium (III)chelates or iron oxide compounds) may be incorporated into or onto thedevice, such as, for example, as a component in a coating or within thevoid volume of the device (e.g., within a lumen, reservoir, or withinthe structural material used to form the device). In some embodiments, amedical device may include radio-opaque or MRI visible markers (e.g.,bands) that may be used to orient and guide the device during theimplantation procedure.

In another embodiment, these agents can be contained within the samecoating layer as the therapeutic agent or they may be contained in acoating layer (as described above) that is either applied before orafter the therapeutic agent containing layer.

The medical implants may, alternatively, or in addition, be visualizedunder visible light, using fluorescence, or by other spectroscopicmeans. Visualization agents that can be included for this purposeinclude dyes, pigments, and other colored agents. In one aspect, themedical implant may further include a colorant to improve visualizationof the implant in vivo and/or ex vivo. Frequently, implants can bedifficult to visualize upon insertion, especially at the margins ofimplant. A coloring agent can be incorporated into a medical implant toreduce or eliminate the incidence or severity of this problem. Thecoloring agent provides a unique color, increased contrast, or uniquefluorescence characteristics to the device. In one aspect, a solidimplant is provided that includes a colorant such that it is readilyvisible (under visible light or using a fluorescence technique) andeasily differentiated from its implant site. In another aspect, acolorant can be included in a liquid or semi-solid composition. Forexample, a single component of a two component mixture may be colored,such that when combined ex-vivo or in-vivo, the mixture is sufficientlycolored.

The coloring agent may be, for example, an endogenous compound (e.g., anamino acid or vitamin) or a nutrient or food material and may be ahydrophobic or a hydrophilic compound. Preferably, the colorant has avery low or no toxicity at the concentration used. Also preferred arecolorants that are safe and normally enter the body through absorptionsuch as β-carotene. Representative examples of colored nutrients (undervisible light) include fat soluble vitamins such as Vitamin A (yellow);water soluble vitamins such as Vitamin B12 (pink-red) and folic acid(yellow-orange); carotenoids such as β-carotene (yellow-purple) andlycopene (red). Other examples of coloring agents include naturalproduct (berry and fruit) extracts such as anthrocyanin (purple) andsaffron extract (dark red). The coloring agent may be a fluorescent orphosphorescent compound such as α-tocopherolquinol (a Vitamin Ederivative) or L-tryptophan. Derivatives, analogues, and isomers of anyof the above colored compound also may be used. The method forincorporating a colorant into an implant or therapeutic composition maybe varied depending on the properties of and the desired location forthe colorant. For example, a hydrophobic colorant may be selected forhydrophobic matrices. The colorant may be incorporated into a carriermatrix, such as micelles. Further, the pH of the environment may becontrolled to further control the color and intensity.

In one aspect, the composition of the present invention include one ormore coloring agents, also referred to as dyestuffs, which will bepresent in an effective amount to impart observable voloration to thecomposition, e.g., the gel. Example of coloring agents include dyessuitable for food such as those known as F.D. & C. dyes and naturalcoloring agents such as grape skin extract, beet red powder, betacarotene, annato, carmine, turmeric, paprika, and so forth. Derivatives,analogues, and isomers of any of the above colored compound also may beused. The method for incorporating a colorant into an implant ortherapeutic composition may be varied depending on the properties of andthe desired location for the colorant. For example, a hydrophobic colorand may be selected for hydrophobic matrices. The colorant may beincorporated into a carrier matrix, such as micelles. Further, the pH ofthe environment may be controlled to further control the color andintensity.

In one aspect, the compositions of the present invention include one ormore preservatives or bacteriostatic agents, present in an effectiveamount to preserve the composition and/or inhibit bacterial growth inthe composition, for example, bismuth tribromophenate, methylhydroxybenzoate, bacitracin, ethyl hydroxybenzoate, propylhydroxybenzoate, erythromycin, 5-fluorouracil, methotrexate,doxorubicin, mitoxantrone, rifamycin, chlorocresol, benzalkoniumchlorides, and the like. Examples of the preservative includeparaoxybenzoic acid esters, chlorobutanol, benzylalcohol, phenethylalcohol, dehydroacetic acid, sorbic acid, etc. In one aspect, thecompositions of the present invention include one or more bactericidal(also known as bacteriacidal) agents.

In one aspect, the compositions of the present invention include one ormore antioxidants, present in an effective amount. Examples of theantioxidant include sulfites, alpha-tocopherol and ascorbic acid.

Within certain aspects of the present invention, the therapeuticcomposition should be biocompatible, and release one or more paclitaxelderivatives over a period of several hours, days, or, months. Asdescribed above, “release of an agent” refers to any statisticallysignificant presence of the agent, or a subcomponent thereof, which hasdisassociated from the compositions. The compositions of the presentinvention may release the paclitaxel derivative at one or more phases,the one or more phases having similar or different performance (e. g.,release) profiles. The therapeutic agent may be made available to thetissue at amounts which may be sustainable, intermittent, or continuous;in one or more phases; and/or rates of delivery; effective to reduce orinhibit any one or more components of fibrosis (or scarring), including:formation of new blood vessels (angiogenesis), migration andproliferation of connective tissue cells (such as fibroblasts or smoothmuscle cells), deposition of extracellular matrix (ECM), and remodeling(maturation and organization of the fibrous tissue).

Thus, release rate may be programmed to impact fibrosis (or scarring) byreleasing a paclitaxel derivative at a time such that at least one ofthe components of fibrosis is inhibited or reduced. Moreover, thepredetermined release rate may reduce agent loading and/or concentrationas well as potentially providing minimal drug washout and thus,increases efficiency of drug effect. Any one of the at least onepaclitaxel derivatives may perform one or more functions, includinginhibiting the formation of new blood vessels (angiogenesis), inhibitingthe migration and proliferation of connective tissue cells (such asfibroblasts or smooth muscle cells), inhibiting the deposition ofextracellular matrix (ECM), and inhibiting remodeling (maturation andorganization of the fibrous tissue). In one embodiment, the rate ofrelease may provide a sustainable level of the paclitaxel derivative tothe susceptible tissue site. In another embodiment, the rate of releaseis substantially constant. The rate may decrease and/or increase overtime, and it may optionally include a substantially non-release period.The release rate may comprise a plurality of rates. In an embodiment,the plurality of release rates may include rates selected from the groupconsisting of substantially constant, decreasing, increasing,substantially non-releasing.

The total amount of paclitaxel derivative made available on, in or nearthe device may be in an amount ranging from about 0.01 μg (micrograms)to about 2500 mg (milligrams). Generally, the paclitaxel derivative maybe in the amount ranging from 0.01 μg to about 10 μg; or from 10 μg toabout 1 mg; or from 1 mg to about 10 mg; or from 10 mg to about 100 mg;or from 100 mg to about 500 mg; or from 500 mg to about 2500 mg.

The total surface amount of paclitaxel derivative on, in or near thedevice may be in an amount ranging from less than 0.01 μg to about 2500μg per mm² of device surface area. Generally, the paclitaxel derivativemay be in the amount ranging from less than 0.01 μg; or from 0.01 μg toabout 10 μg; or from 10 μg to about 250 μg; or from 250 μg to about 2500μg.

The paclitaxel derivative that is on, in or near the device may bereleased from the composition in a time period that may be measured fromthe time of implantation, which ranges from about less than 1 day toabout 180 days. Generally, the release time may also be from about lessthan 1 day to about 7 days; from 7 days to about 14 days; from 14 daysto about 28 days; from 28 days to about 56 days; from 56 days to about90 days; from 90 days to about 180 days. In certain embodiments, thedrug is released in effective concentrations for a period ranging fromabout 1 to about 90 days.

The amount of paclitaxel derivative released from the composition as afunction of time may be determined based on the in vitro releasecharacteristics of the agent from the composition. The in vitro releaserate may be determined by placing the paclitaxel derivative within thecomposition or device in an appropriate buffer such as 0.1M phosphatebuffer (pH 7.4)) at 37° C. Samples of the buffer solution are thenperiodically removed for analysis by HPLC, and the buffer is replaced toavoid any saturation effects.

Based on the in vitro release rates, the release of paclitaxelderivative per day may range from an amount ranging from about 0.01 μg(micrograms) to about 2500 mg (miiligrams). Generally, the paclitaxelderivative that may be released in a day may be in the amount rangingfrom 0.01 μg to about 10 μg; or from 10 μg to about 1 mg; or from 1 mgto about 10 mg; or from 10 mg to about 100 mg; or from 100 mg to about500 mg; or from 500 mg to about 2500 mg.

In one embodiment, the paclitaxel derivative is made available to thesusceptible tissue site in a programmed, sustained, and/or controlledmanner which results in increased efficiency and/or efficacy. Further,the release rates may vary during either or both of the initial andsubsequent release phases. There may also be additional phase(s) forrelease of the same substance(s) and/or different substance(s).

Further, therapeutic compositions and devices of the present inventionshould preferably be have a stable shelf-life for several months andcapable of being produced and maintained under sterile conditions. Manypharmaceuticals are manufactured to be sterile and this criterion isdefined by the USP XXII <1211>. The term “USP” refers to U.S.Pharmacopeia (see www.usp.org, Rockville, Md.). Sterilization may beaccomplished by a number of means accepted in the industry and listed inthe USP XXII <1211>, including gas sterilization, ionizing radiation or,when appropriate, filtration. Sterilization may be maintained by what istermed asceptic processing, defined also in USP XXII <1211>. Acceptablegases used for gas sterilization include ethylene oxide. Acceptableradiation types used for ionizing radiation methods include gamma, forinstance from a cobalt 60 source and electron beam. A typical dose ofgamma radiation is 2.5 MRad. Filtration may be accomplished using afilter with suitable pore size, for example 0.22 μm and of a suitablematerial, for instance polytetrafluoroethylene (e.g., TEFLON from E. I.DuPont De Nemours and Company, Wilmington, Del.).

D. Methods of Utilizing Stent Devices

There are numerous types of stents where the occurrence of a fibroticreaction will adversely affect the functioning of the device or thebiological problem for which the device was implanted or used. Thecoating of paclitaxel derivatives such as paclitaxel derivatives onto orincorporation of paclitaxel derivatives into stent devices provides asolution to the clinical problems that can be encountered with thesedevices.

Generally, stents are inserted in a similar fashion regardless of thesite or the disease being treated. Briefly, a preinsertion examination,usually a diagnostic imaging procedure, endoscopy, or directvisualization at the time of surgery, is generally first performed inorder to determine the appropriate positioning for stent insertion. Aguidewire is then advanced through the lesion or proposed site ofinsertion, and over this is passed a delivery catheter which allows astent in its collapsed form to be inserted. Intravascular stents may beinserted into an artery such as the femoral artery in the groin andadvanced through the circulation under radiological guidance until theyreach the anatomical location of the plaque in the coronary orperipheral circulation. Typically, stents are capable of beingcompressed, so that they can be inserted through tiny cavities via smallcatheters, and then expanded to a larger diameter once they are at thedesired location. The delivery catheter then is removed, leaving thestent standing on its own as a scaffold. Once expanded, the stentphysically forces the walls of the passageway apart and holds them open.A post insertion examination, usually an x-ray, is often utilized toconfirm appropriate positioning.

Stents are typically maneuvered into place under, radiologic or directvisual control, taking particular care to place the stent preciselywithin the vessel being treated. In certain aspects the stent canfurther include a radio-opaque, echogenic material, or MRI responsivematerial (e.g., MRI contrast agent) to aid in visualization of thedevice under ultrasound, fluoroscopy and/or magnetic resonance imaging.The radio-opaque or MRI visible material may be in the form of one ormore markers (e.g., bands of material that are disposed on either end ofthe stent) that may be used to orient and guide the device during theimplantation procedure.

In another aspect, the paclitaxel derivative or a composition comprisinga paclitaxel derivative may be infiltrated into or onto tissuesurrounding the stent. Alternatively, the tissue cavity into which thestent is placed can be treated with a paclitaxel derivative prior to,during, or after the procedure.

Infiltration of paclitaxel derivatives or compositions comprisingpaclitaxel derivatives may be accomplished, for example, usingdrug-delivery catheters for local, regional or systemic delivery offibrosis inhibiting agents to the tissue surrounding the device. Thedrug delivery catheter may be advanced through the circulation ofinserted directly into tissues under radiological guidance (e.g.,magnetic, ultrasonic or MRI) until they reach the desired anatomicallocation. The paclitaxel derivative can then be released from thecatheter lumen in high local concentrations in order to delivertherapeutic doses of the drug to the tissue surrounding the device orimplant. Alternatively, or in addition, the paclitaxel derivative orcomposition comprising the paclitaxel derivative may be injecteddirectly into the treatment site (e.g., into the space around the stentor into tissue surrounding the stent) under endoscopic vision.

Other methods of infiltrating paclitaxel derivatives into the treatmentsite include (a) topical application of the paclitaxel derivative intothe anatomical space where the device will be placed (particularlyuseful for this embodiment is the use of polymeric carriers whichrelease the anti-fibrosing agent over a period ranging from severalhours to several weeks. Compositions that can be used for thisapplication include, e.g., fluids, microspheres, pastes, gels,hydrogels, crosslinked gels, microparticulates, sprays, aerosols, solidimplants and other formulations which release a fibrosis inhibitingagent into the region where the device or implant will be implanted);(b) microparticulate forms of the therapeutic agent are also useful fordirected delivery into the implantation site; (c) sprayablecollagen-containing formulations such as COSTASIS (from AngiotechPharmaceuticals, Inc., Canada), either alone, or loaded with apaclitaxel derivative, applied to the implantation site (or theimplant/device surface); (d) sprayable PEG-containing formulations suchas COSEAL (Angiotech Pharmaceuticals, lnc.), SPRAYGEL or DURASEAL (bothfrom Confluent Surgical, Inc., Boston, Mass.), FOCALSEAL (GenzymeCorporation, Cambridge, Mass.) either alone, or loaded with a paclitaxelderivative, applied to the implantation site (or the implant/devicesurface); (e) fibrin-containing formulations such as FLOSEAL or TISSEEL(both from Baxter Healthcare Corporation, Fremont, Calif.), eitheralone, or loaded with a paclitaxel derivative, applied to theimplantation site (or the implant/device surface); (f) hyaluronicacid-containing formulations such as RESTYLANE or PERLANE (both fromQ-Med AB, Sweden), HYLAFORM (Inamed Corporation (Santa Barbara,Calif.)), SYNVISC (Biomatrix, Inc., Ridgefield, N.J.), SEPRAFILM orSEPRACOAT (both from Genzyme Corporation, Cambridge, Mass.), INTERGEL(Lifecore Biomedical) loaded with a paclitaxel derivative applied to theimplantation site (or the implant/device surface); (g) polymeric gelsfor surgical implantation such as REPEL (Life Medical Sciences, Inc.,Princeton, N.J.) or FLOGEL (Baxter Healthcare Corporation) loaded with apaclitaxel derivative applied to the implantation site (or theimplant/device surface); (h) surgical adhesives containingcyanoacrylates such as DERMABOND (Johnson & Johnson, Inc., NewBrunswick, N.J.), INDERMIL (U.S. Surgical Company, Norwalk, Conn.),GLUSTITCH (Blacklock Medical Products Inc., Canada), TISSUMEND II(Veterinary Products Laboratories,, Phoenix, Ariz.), VETBOND (3MCompany, St. Paul, Minn.), HISTOACRYL BLUE (Davis & Geck, St. Louis,Mo.) and ORABASE SMOOTHE N-SEAL Liquid Protectant (Colgate-PalmoliveCompany, New York, N.Y.), either alone, or loaded with a paclitaxelderivative, applied to the implantation site (or the implant/devicesurface).

Drugs and Dosage

As described above, any paclitaxel derivative described above can becombined with a stent device. Further, stent devices may be adapted torelease a paclitaxel derivative that inhibits one or more of the fourgeneral components of the process of fibrosis (or scarring), including:formation of new blood vessels (angiogenesis), migration andproliferation of connective tissue cells (such as fibroblasts or smoothmuscle cells), deposition of extracellular matrix (ECM), and remodeling(maturation and organization of the fibrous tissue). By inhibiting oneor more of the components of fibrosis (or scarring), the overgrowth ofgranulation tissue may be inhibited or reduced.

As stent devices are made in a variety of configurations and sizes, theexact dose administered will vary with device size, surface area anddesign. However, certain principles can be applied in the application ofthis art. Drug dose can be calculated as a function of dose per unitarea (of the portion of the device being coated), total drug doseadministered, and appropriate surface concentrations of active drug canbe determined. Drugs are to be used at concentrations that range fromseveral times more than 10%, 5%, or even less than 1% of theconcentration typically used in a single chemotherapeutic systemic doseapplication.

Several examples of agents for use with stents include the following:9-deoxotaxol, 7-deoxy-9-deoxotaxol, and10-desacetoxy-7-deoxy-9-deoxotaxol.

Regardless of the method of application of the drug to the intravasculardevice, the exemplary agents, used alone or in combination, should beadministered under the following dosing guidelines. The total dose ofagent in or on the device may be in the range of about 0.01 μg-10 μg, or10 μg-250 μg, or 250 μg-1 mg, or 1 mg-10 mg, or 10 mg-250 mg, or 250mg-1000 mg, or 1000 mg-2500 mg. The dose of paclitaxel derivative perunit area of device surface to which the agent is applied may be in therange of about 0.01 μg/mm²-1 μg/mm², or 1 μg/mm²-10 μg/mm², or 10μg/mm²-250 μg/mm²; 250 μg/mm²-1000 μg/mm², or 1000 μg/mm²-2500 μg/mm².

Provided below are exemplary dosage ranges for various paclitaxelderivatives that can be used in conjunction with stent devices inaccordance with the invention. A) paclitaxel derivatives (e.g.,9-deoxotaxol, 7-deoxy-9-deoxotaxol, and10-desacetoxy-7-deoxy-9-deoxotaxol): total dose not to exceed 10 mg(range of 0.1 μg to 10 mg); preferred 1 μg to 3 mg. The dose per unitarea of the device of 0.1 μg-10 μg per mm²; preferred dose of 0.25μg/mm²-5 μg/mm². Minimum concentration of 10⁻⁸-10⁻⁴ M of paclitaxel isto be maintained on the device surface.

It should be apparent to one of skill in the art that potentially anypaclitaxel derivative described above can be utilized alone; or incombination, in the practice of this embodiment. In various aspect, thepresent invention provides a medical device contain a paclitaxelderivative as described herein in a dosage as set forth above.

The following examples are offered by way of illustration, and not byway of limitation.

EXAMPLES Example 1 Parylene Coating

The metallic portion of a coronary stent is washed by dipping it intoHPLC grade isopropanol. The cleaned device is then coated with aparylene coating using a parylene coater and either di-p-xylylene ordichloro-di-p-xylylene as the coating feed material. This procedure maybe used to coat other types of stents that include a metallic portion(e.g., peripheral stents, covered stents).

Example 2 Paclitaxel Coating—End Coating

Solutions are prepared by dissolving 9-deoxotaxol in 5 mL HPLC gradeTHF. The ends of a parylene coated coronary stent (prepared as inExample 1) are then dipped into the paclitaxel derivative/THF solution.After various incubation times, the devices are removed and dried in aforced air oven (50° C.). The device is then further dried in a vacuumoven overnight. The amount of 9-deoxotaxol used in each solution isvaried such that the amount of 9-deoxotaxol coated onto the ends of thedevice is in the range of 0.06 mg/mm² to 10 mg/mm². This procedure maybe used to coat other types of devices that include a metallic portion(e.g., peripheral stents, covered stents).

Example 3 Paclitaxel Coating—Complete Coating

Paclitaxel derivative solutions are prepared by dissolving 9-deoxotaxolin 5 mL HPLC grade THF. A parylene coated coronary stent (as prepared inExample 1) is then dipped entirely into the paclitaxel/THF solution.After various incubation times, the device is removed and dried in aforced air oven (50° C.). The device is then further dried in a vacuumoven overnight. The amount of paclitaxel used in each solution is variedsuch that the amount of paclitaxel coated onto the ends of the device isin the range of 0.06 mg/mm² to 10 mg/mm². In addition to paclitaxel, thefollowing are exemplary compounds that may be also used to coat thedevice: 7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.This procedure may be used to coat other types of parylene coateddevices that include a metallic portion (e.g., peripheral stents,covered stents).

Example 4 Application of a Parylene Overcoat

A paclitaxel derivative coated device is placed in a parylene coater andan additional thin layer of parylene is deposited on the paclitaxelcoated device (see Example 2 or 3). The coating duration is altered suchthat the parylene top-coat thickness is varied such that differentelution profiles of the paclitaxel may be obtained.

Example 5 Application of an Echogenic Coating Layer

DESMODUR (Bayer AG, Germany), an isocyanate pre-polymer, is dissolved ina 50:50 mixture of dimethylsulfoxide and tetrahydrofuran. Apaclitaxel/parylene overcoated coronary stent (prepared as in Example 4)is then dipped into the pre-polymer solution. The device is then removedand the coating is then partially dried at room temperature for 3 to 5minutes. The device is then immersed in a beaker of water (roomtemperature) for 3-5 minutes to cause the polymerization reaction tooccur rapidly. An echogenic coating is formed. This procedure may beused to coat other types of devices (e.g., peripheral stents, coveredstents).

Example 6 Paclitaxel/Polymer Coating—End Coating

5% solutions of poly(ethylene-co-vinyl acetate) (EVA) (60% vinylacetate) are prepared using THF as the solvent. Various amounts of9-deoxotaxol are added to each of the EVA solutions. The ends of acoronary stent are dipped into the 9-deoxotaxol/EVA solution. Afterremoving the end-coated device from the solution, the coating is driedby placing the device in a forced air oven (40° C.) for 3 hours. Thecoated device is then further dried under vacuum for 24 hours. The dipcoating process may be repeated to increase the amount ofpolymer/9-deoxotaxol coated onto the device. In addition to9-deoxotaxol, the following are exemplary compounds that may also beused to coat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol. This procedure may be used to coatedother types of devices (e. g., peripheral stents, nasal stents).

Example 7 Paclitaxel-Heparin Coating—End Coating

5% solutions of poly(ethylene-co-vinyl acetate) (EVA) (60% vinylacetate) are prepared using THF as the solvent. Various amounts of9-deoxotaxol and a solution of tridodecyl methyl ammoniumchloride-heparin complex (PolySciences) are added to each of the EVAsolutions. The ends of a stent device are dipped into the9-deoxotaxol/EVA solution. After removing the end-coated device from thesolution, the coating is dried by placing the device in a forced airoven (40° C.) for 3 hours. The coated stent is then further dried undervacuum for 24 hours. In addition to 9-deoxotaxol, the following areexemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol. Thisprocedure may be used to coated other types of devices includingcoronary stents and peripheral stents.

Example 8 Paclitaxel—Heparin/Heparin Coating

The uncoated portions of 9-deoxotaxol-heparin coated devices (Example 7)are dipped into a 5% EVA solution containing different amounts of atridodecyl methyl ammonium chloride-heparin complex solution(PolySciences). After removing the end-coated device from the solution,the coating is dried by placing the stent device in a forced air oven(40° C.) for 3 hours. The coated device is then further dried undervacuum for 24 hours. This provides a device with a 9-deoxotaxol/heparincoating on the ends of the device and a heparin coating on the remainingparts of the device. In addition to 9-deoxotaxol, the following areexemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol. Thisprocedure may be used to coat other types of devices including coronarystents and peripheral stents.

Example 9 Paclitaxel Derative/Polymer Coating—End Coating

5% solutions of poly(styrene-co-isobutylene-styrene) (SIBS) are preparedusing THF as the solvent. Various amounts of 9-deoxotaxol are added toeach of the SIBS solutions. The ends of a central venous catheter deviceare dipped into the paclitaxel/SIBS solution. After removing theend-coated device from the solution, the coating is dried by placing thedevice in a forced air oven (40° C.) for 3 hours. The coated device isthen further dried under vacuum for 24 hours. The dip coating processmay be repeated to increase the amount of polymer/9-deoxotaxol coatedonto the device. In addition to 9-deoxotaxol, the following areexemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol. Thisprocedure may be used to coat other types of devices including coronarystents, non-vascular stents, and peripheral stents.

Example 10 Paclitaxel Derivative/Polymer Coating—Echogenic Coating

A coated stent from Example 9 is dipped into a DESMODUR solution (50:50mixture of dimethylsulfoxide and tetrahydrofuran). The device is thenremoved and the coating is then partially dried at room temperature for3 to 5 minutes. The device is then immersed in a beaker of water (roomtemperature) for 3-5 minutes to cause the polymerization reaction tooccur rapidly. An echogenic coating is formed. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 11 Polymer/Echogenic Coating

5% solutions of poly(styrene-co-isobutylene-styrene) (SIBS) are preparedusing THF as the solvent. A Gl stent device is dipped into the SIBSsolution. After removing the device from the solution, the coating isdried by placing the device in a forced air oven (40° C.) for 3 hours.The coated device is then further dried under vacuum for 24 hours.

The coated device is dipped into a DESMODUR solution (50:50 mixture ofdimethylsulfoxide and tetrahydrofuran). The device is then removed andthe coating is then partially dried at room temperature for 3 to 5minutes. The device is then immersed in a beaker of water (roomtemperature) for 3-5 minutes to cause the polymerization reaction tooccur rapidly. The device is dried under vacuum for 24 hours at roomtemperature. The ends of the coated device are immersed into a solutionof 9-deoxotaxol. The device is removed and dried at 40° C. for 1 hourand then under vacuum for 24 hours.

The amount of 9-deoxotaxol absorbed by the polymeric coating may bealtered by changing the 9-deoxotaxol concentration, the immersion timeas well as the solvent composition of the solution. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol. This procedure may be used to coatother types of devices including coronary stents, peripheral stents, andtracheal/bronchial stents, nasal stents, and fallopian tube stents.

Example 12 Paclitaxel/Siloxane Coating—End Coating

A tracheal stent is coated with a siloxane layer by exposing the deviceto gaseous tetramethylcyclotetrasiloxane that is then polymerized by lowenergy plasma polymerization onto the device surface. The thickness ofthe siloxane layer may be increased by increasing the polymerizationtime. The ends of the device are then immersed into a 9-deoxotaxol/THFsolution. The 9-deoxotaxol is absorbed into the siloxane coating. Thedevice is then removed from the solution and is dried for 2 hours at 40°C. in a forced air oven. The device is then further dried under vacuumat room temperature for 24 hours. The amount of 9-deoxotaxol coated ontothe device ends may be varied by altering the concentration of thepaclitaxel/THF solution as well as altering the immersion time of thedevice ends in the paclitaxel THF solution. In addition to 9-deoxotaxol,the following are exemplary compounds that may be used to coat thedevice: 7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.This procedure may be used to coat other types of devices includingcoronary stents and peripheral stents.

Example 13 Heparin Coating

A tracheal stent is dipped into a solution containing different amountsof a tridodecyl methyl ammonium chloride-heparin complex solution(PolySciences). After various incubation times, the device is removedand dried in a forced air oven (50° C.). The device is then furtherdried in a vacuum oven overnight. Other types of devices that may becoated with this procedure include coronary stents, peripheral stents,nasal and sinus stents, and bronchial stents.

Example 14 Spray-Coated Devices

2% solutions poly(styrene-co-isobutylene-styrene) (SIBS) are preparedusing THF as the solvent. Various amounts of 9-deoxotaxol are added toeach solution. A biliary stent held with a pair of tweezers and is thenspray coated with one of the paclitaxel/polymer solutions using anairbrush. The device is then air-dried. The device is then held in a newlocation using the tweezers and a second coat of paclitaxel/polymer isapplied. The device is air-dried and is then dried under vacuumovernight. The total amount of 9-deoxotaxol coated onto the device maybe altered by changing the paclitaxel content in the solution as well asby increasing the number of coatings applied. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 15 Drug Coated Covered Stent-Non-Degradable

A covered stent (WALLGRAFT, Boston Scientific Corporation) is attachedto a rotating mandrel. A solution of paclitaxel (5% w/w) in apolyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) is then sprayedonto the outer surface of the covered stent. The solution is sprayed onat a rate that ensures that the graft material is not damaged orsaturated with the sprayed solution. The covered stent is allowed to airdry after which it is dried under vacuum for 24 hours. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 16 Drug Coated Covered Stent-Degradable

A WALLGRAFT stent is attached to a rotating mandrel. Paclitaxel (5% w/w)in a PLGA/ethyl acetate solution (2.5% w/v) is then sprayed onto theouter surface of the covered stent. The solution is sprayed on at a ratethat ensures that the graft material is not damaged or saturated withthe sprayed solution. The covered stent is allowed to air dry afterwhich it is dried under vacuum for 24 hours. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 17 Drug Coated Covered Stent—Degradable Overcoat

A drug-coated WALLGRAFT stent from either Example 15 or Example 16 isattached to a rotating mandrel. A PLGA/ethyl acetate solution (2.5% w/v)is then sprayed onto the outer surface of the covered stent such that acoating is formed over the initial drug containing coating. The solutionis sprayed on at a rate that ensures that the graft material is notdamaged or saturated with the sprayed solution. The covered stent isallowed to air dry after which it is dried under vacuum for 24 hours.

Example 18 Drug-Loaded Microsphere Formulation

9-deoxotaxol (10% w/w) is added to a solution of PLGA (50/50, Mw≈54,000)in DCM (5% w/v). The solution is vortexed and then poured into a stirred(overhead stirrer with a 3 bladed TEFLON coated stirrer) aqueous PVA(approximately 89% hydrolyzed, Mw≈13,000, 2% w/v). The solution isstirred for 6 hours after which the solution is centrifuged to sedimentthe microspheres. The microspheres were resuspended in water. Thecentrifugation-washing process is repeated 4 times. The finalmicrosphere solution is flash frozen in an acetone/dry-ice bath. Thefrozen solution is then freeze-dried to produce a fine powder. The sizeof the microspheres formed may be altered by changing the stirring speedand/or the PVA solution concentration. The freeze dried powder may beresuspended in PBS or saline and may be used for direct injection, as anincubation fluid or as an irrigation fluid. In addition to 9-deoxotaxol,the following are exemplary compounds that may be used to coat thedevice: 7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 19 Drug Coated Stent (Exterior Coating)

A coronary stent is dipped into a polyurethane (CHRONOFLEX 85A)/THFsolution (2.5% w/v). The coated stent is allowed to air dry for 10seconds. The stent is then rolled in powdered 9-deoxotaxol that isspread thinly on a piece of release liner. The rolling process is donein such a manner that the paclitaxel powder predominantly adheres to theexterior side of the coated stent. The stents are air-dried for 1 hourfollowed by vacuum drying for 24 hours. In addition to 9-deoxotaxol, thefollowing are exemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 20 Drug Coated Stent (Exterior Coating) With a Heparin Coating

The drug-coated stent from Example 19 is further coated with a heparincoating. The stents that are prepared in Example 19 are dipped into asolution of heparin-benzalkonium chloride complex (1.5% (w/v) inisopropanol, STS Biopolymers). The stents are removed from the solutionand are air-dried for 1 hour followed by vacuum drying for 24 hours.This process results in both the interior and exterior surfaces of thecovered stent being coated with heparin.

Example 21 Partial Drug Coating of a Covered Stent

A WALLGRAFT covered stent is attached to a rotating mandrel. A masksystem is set up so that only the middle of the outer surface of thecovered stent may be sprayed. A solution of 9-deoxotaxol (5% w/w) in apolyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) is then sprayedonto the outer surface of the covered stent. The solution is sprayed onat a rate that ensures that the graft material is not damaged orsaturated with the sprayed solution. The covered stent is allowed to airdry after which it is dried under vacuum for 24 hours. In addition to9-deoxotaxol, the following are exemplary compounds that may be used tocoat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 22 Paclitaxel Derivative Coated Covered Stent

A WALLGRAFT covered stent is attached to a rotating mandrel. A masksystem is set up so that only the middle of the outer surface of thecovered stent may be sprayed. A solution of 9-deoxotaxol (5% w/w) in apolyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) is then sprayedonto the outer surface of the covered stent. The solution is sprayed onat a rate that ensures that the graft material is not damaged orsaturated with the sprayed solution. The covered stent is allowed to airdry. The mask is then rearranged so that only the ends of the outersurface of the covered stent may be sprayed. The ends of the outersurface of the covered stent are then sprayed with a dexamethasone (10%w/w)/polyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v). The sampleis air dried after which it is dried under vacuum for 24 hours. Inaddition to 9-deoxotaxol, the following are exemplary compounds that maybe used to coat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 23 Drug-Heparin Coated Covered Stent

A WALLGRAFT covered stent is attached to a rotating mandrel. A masksystem is set up so that only the middle of the outer surface of thecovered stent may be sprayed. A solution of 9-deoxotaxol (5% w/w) in apolyurethane (CHRONOFLEX 85A)/THF solution (2.5% w/v) is then sprayedonto the outer surface of the covered stent. The solution is sprayed onat a rate that ensures that the graft material is not damaged orsaturated with the sprayed solution. The covered stent is allowed to airdry. The mask is then rearranged so that only the ends of the outersurface of the covered stent may be sprayed. The ends of the outersurface of the covered stent are then sprayed with aheparin-benzalkonium chloride complex (1.5% (w/v) in isopropanol, STSBiopolymers). The sample is air dried after which it is dried undervacuum for 24 hours. In addition to 9-deoxotaxol, the following areexemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 24 Drug-Dexamethaxone Coated Covered Stent

A WALLGRAFT stent is attached to a rotating mandrel. A solution of9-deoxotaxol (5% w/w) and dexamethazone (5% w/w) in a PLGA (50/50,Mw≈54,000)/ ethyl acetate solution (2.5% w/v) is sprayed onto the outersurface of the covered stent. The solution is sprayed on at a rate thatensures that the graft material is not damaged or saturated with thesprayed solution. The covered stent is allowed to air dry after which itis dried under vacuum for 24 hours. In addition to 9-deoxotaxol, thefollowing are exemplary compounds that may be used to coat the device:7-deoxy-9-deoxotaxol and 10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 25 Drug-Dexamethasone Coated Covered Stent (Sequential Coating)

A WALLGRAFT stent is attached to a rotating mandrel. A solution of9-deoxotaxol (5% w/w) in a PLGA (50/50, Mw≈54,000)/ethyl acetatesolution (2.5% w/v) is sprayed onto the outer surface of the coveredstent. The solution is sprayed on at a rate that ensures that the graftmaterial is not damaged or saturated with the sprayed solution. Thecovered stent is allowed to air dry. A methanol solution ofdexamethasone is then sprayed onto the outer surface of the coveredstent (at a rate that ensures that the graft material is not damaged orsaturated with the sprayed solution). The covered stent is allowed toair dry after which it is dried under vacuum for 24 hours. In additionto 9-deoxotaxol, the following are exemplary compounds that may be usedto coat the device: 7-deoxy-9-deoxotaxol and10-desacetoxy-7-deoxy-9-deoxotaxol.

Example 26 Screening Assay for Assessing the Effect of PaclitaxelCompounds on Nitric Oxide Production by Macrophages

The murine macrophage cell line RAW 264.7 was trypsinized to removecells from flasks and plated in individual wells of a 6-well plate.Approximately 2×10⁶ cells were plated in 2 mL of media containing 5%heat-inactivated fetal bovine serum (FBS). RAW 264.7 cells wereincubated at 37° C. for 1.5 hours to allow adherence to plastic.Paclitaxel was prepared in DMSO at a concentration of 10⁻² M andserially diluted 10-fold to give a range of stock concentrations (10⁻⁸ Mto 10⁻² M). Media was then removed and cells were incubated in 1 ng/mLof recombinant murine IFNγ and 5 ng/mL of LPS with or without paclitaxelin fresh media containing 5% FBS. Paclitaxel was added to cells bydirectly adding paclitaxel DMSO stock solutions, prepared earlier, at a1/1000 dilution, to each well. Plates containing IFNγ, LPS plus or minuspaclitaxel were incubated at 37° C. for 24 hours (Chem. Ber. (1879) 12:426; J. AOAC (1977) 60-594; Ann. Rev. Biochem. (1994) 63: 175).

At the end of the 24 hour period, supernatants were collected from thecells and assayed for the production of nitrites. Each sample was testedin triplicate by aliquoting 50 μL of supernatant in a 96-well plate andadding 50 μL of Greiss Reagent A (0.5 g sulfanilamide, 1.5 ml H₃PO₄,48.5 ml ddH₂O) and 50 μL of Greiss Reagent B (0.05 gN-(1-naphthyl)-ethylenediamine, 1.5 mL H₃PO₄, 48.5 mL ddH₂ O). Opticaldensity was read immediately on microplate spectrophotometer at 562 nmabsorbance. Absorbance over triplicate wells was averaged aftersubtracting background and concentration values were obtained from thenitrite standard curve (1 μM to 2 mM). Inhibitory concentration of 50%(IC₅₀) was determined by comparing average nitrite concentration to thepositive control (cell stimulated with IFNγ and LPS). An average of n=4replicate experiments was used to determine IC₅₀ values for paclitaxel:IC₅₀ (nM): 7 nM.

Example 27 Surgical Adhesions Model to Assess Fibrosis Inhibiting Agents

The rabbit uterine horn model is used to assess the anti-fibroticcapacity of formulations in vivo. Mature New Zealand White (NZW) femalerabbits are placed under general anesthetic. Using aseptic precautions,the abdomen is opened in two layers at the midline to expose the uterus.Both uterine horns are lifted out of the abdominal cavity and assessedfor size on the French Scale of catheters. Horns between #8 and #14 onthe French Scale (2.5-4.5 mm diameter) are deemed suitable for thismodel. Both uterine horns and the opposing peritoneal wall are abradedwith a #10 scalpel blade at a 45° angle over an area 2.5 cm in lengthand 0.4 cm in width until punctuate bleeding is observed. Abradedsurfaces are tamponaded until bleeding stops. The individual horns arethen opposed to the peritoneal wall and secured by two sutures placed 2mm beyond the edges of the abraded area. The formulation is applied andthe abdomen is closed in three layers. After 14 days, animals areevaluated post mortem with the extent and severity of adhesions beingscored both quantitatively and qualitatively.

Example 28 Screening Assay for Assessing the Effect of PaclitaxelCompounds on Cell Proliferation

Fibroblasts at 70-90% confluency were trypsinized, replated at 600cells/well in media in 96-well plates and allowed to attach overnight.Paclitaxel was prepared in DMSO at a concentration of 10⁻² M and diluted10-fold to give a range of stock concentrations (10⁻⁸ M to 10⁻² M). Drugdilutions were diluted 1/1000 in media and added to cells to give atotal volume of 200 μL/well. Each drug concentration was tested intriplicate wells. Plates containing fibroblasts and paclitaxel wereincubated at 37° C. for 72 hours (In vitro toxicol. (1990) 3: 219;Biotech. Histochem. (1993) 68: 29; Anal. Biochem. (1993) 213: 426).

To terminate the assay, the media was removed by gentle aspiration. A1/400 dilution of CYQUANT 400X GR dye indicator (Molecular Probes;Eugene, Oreg.) was added to 1X Cell Lysis buffer, and 200 μL of themixture was added to the wells of the plate. Plates were incubated atroom temperature, protected from light for 3-5 minutes. Fluorescence wasread in a fluorescence microplate reader at ˜480 nm excitationwavelength and ˜520 nm emission maxima. Inhibitory concentration of 50%(IC₅₀) was determined by taking the average of triplicate wells andcomparing average relative fluorescence units to the DMSO control. Anaverage of n=4 replicate experiments was used to determine IC₅₀ values.IC₅₀ (nM): paclitaxel, 23 (FIG. 8)

Example 29 Evaluation of Paclitxel Containing Mesh on IntimalHyperplasia Development in a Rat Balloon Injury Carotid Artery Model

A rat balloon injury carotid artery model was used to demonstrate theefficacy of a paclitaxel containing mesh system on the development ofintimal hyperplasia fourteen days following placement.

Control Group

Wistar rats weighing 400-500 g were anesthetized with 1.5% halothane inoxygen and the left external carotid artery was exposed. A 2 FrenchFogarty balloon embolectomy catheter (Baxter, Irvine, Calif.) wasadvanced through an arteriotomy in the external carotid artery down theleft common carotid artery to the aorta. The balloon was inflated withenough saline to generate slight resistance (approximately 0.02 ml) andit was withdrawn with a twisting motion to the carotid bifurcation. Theballoon was then deflated and the procedure repeated twice more. Thistechnique produced distension of the arterial wall and denudation of theendothelium. The external carotid artery was ligated after removal ofthe catheter. The right common carotid artery was not injured and wasused as a control.

Local Perivascular Paclitaxel Treatment

Immediately after injury of the left common carotid artery, a 1 cm longdistal segment of the artery was exposed and treated with a 1×1 cmpaclitaxel-containing mesh. The wound was then closed the animals werekept for 14 days.

Histology and Immunohistochemistry

At the time of sacrifice, the animals were euthanized with carbondioxide and pressure perfused at 100 mmHg with 10% phosphate bufferedformaldehyde for 15 minutes. Both carotid arteries were harvested andleft overnight in fixative. The fixed arteries were processed andembedded in paraffin wax. Serial cross-sections were cut at 3 μmthickness every 2 mm within and outside the implant region of theinjured left carotid artery and at corresponding levels in the controlright carotid artery. Cross-sections were stained with Mayer'shematoxylin-and-eosin for cell count and with Movat's pentachrome stainsfor morphometry analysis and for extracellular matrix compositionassessment.

Results

From FIGS. 1-3, it is evident that the perivascular delivery ofpaclitaxel using the paclitaxel mesh formulation resulted is a dramaticreduction in intimal hyperplasia.

Example 30 Effect of Paclitaxel and Other Anti-Microtubule Agents onMatrix Metalloproteinase Production

A. Materials and Methods

1. IL-1 stimulated AP-1 transcriptional activity is inhibited bypaclitaxel

Chondrocytes were transfected with constructs containing an AP-1 drivenCAT reporter gene, and stimulated with IL-1, IL-1 (50 ng/ml) was addedand incubated for 24 hours in the absence and presence of paclitaxel atvarious concentrations. Paclitaxel treatment decreased CAT activity in aconcentration dependent manner (mean±SD). The data noted with anasterisk (*) have significance compared with IL-1-induced CAT activityaccording to a t-test, P<0.05. The results shown are representative ofthree independent experiments.

2. Effect of paclitaxel on IL-1 induced AP-1 DNA binding activity, AP-1DNA

Binding activity was assayed with a radiolabeled human AP-1 sequenceprobe and gel mobility shift assay. Extracts from chondrocytes untreatedor treated with various amounts of paclitaxel (10⁻⁷ to 10⁻⁵ M) followedby IL-1β (20 ng/ml) were incubated with excess probe on ice for 30minutes, followed by non-denaturing gel electrophoresis. The “com” lanecontains excess unlabeled AP-1 oligonucleotide. The results shown arerepresentative of three independent experiments.

3. Effect of paclitaxel on IL-1 induced MMP-1 and MMP-3 mRNA expression

Cells were treated with paclitaxel at various concentrations (10⁻⁷ to10⁻⁵ M) for 24 hours, then treated with IL-1β (20 ng/ml) for additional18 hours in the presence of paclitaxel. Total RNA was isolated, and theMMP-1 mRNA levels were determined by Northern blot analysis. The blotswere subsequently stripped and reprobed with ³²P-radiolabeled rat GAPDHeDNA, which was used as a housekeeping gene. The results shown arerepresentative of four independent experiments. Quantitation ofcollagenase-1 and stromelysin-expression mRNA levels. The MMP-1 andMMP-3 expression levels were normalized with GAPDH.

4. Effect of other anti-microtubules on collagenase expression

Primary chondrocyte cultures were freshly isolated from calf cartilage.The cells were plated at 2.5×10⁶ per ml in 100×20 mm culture dishes andincubated in Ham's F12 medium containing 5% FBS overnight at 37° C. Thecells were starved in serum-free medium overnight and then treated withanti-microtubule agents at various concentrations for 6 hours. IL-1 (20ng/ml) was then added to each plate and the plates incubated for anadditional 18 hours. Total RNA was isolated by the acidified guanidineisothiocyanate method and subjected to electrophoresis on a denaturedgel. Denatured RNA samples (15 μg) were analyzed by gel electrophoresisin a 1% denatured gel, transferred to a nylon membrane and hybridizedwith the ³²P-labeled collagenase cDNA probe. ³²P-labeled glyceraldehydephosphate dehydrase (GAPDH) cDNA as an internal standard to ensureroughly equal loading. The exposed films were scanned and quantitativelyanalyzed with IMAGEQUANT.

B. Results

1. Promoters on the family of matrix metalloproteinases

FIG. 4A shows that all matrix metalloproteinases contained thetranscriptional elements AP-1 and PEA-3 with the exception of GelatinaseB. It has been well established that expression of matrixmetalloproteinases such as collagenases and stromelysins are dependenton the activation of the transcription factors AP-1. Thus inhibitors ofAP-1 may inhibit the expression of matrix metalloproteinases.

2. Effect of paclitaxel on AP-1 transcriptional activity

As demonstrated in FIG. 4B, IL-1 stimulated AP-1 transcriptionalactivity 5-fold. Pretreatment of transiently transfected chondrocyteswith paclitaxel reduced IL-1 induced AP-1 reporter gene CAT activity.Thus, IL-1 induced AP-1 activity was reduced in chondrocytes bypaclitaxel in a concentration dependent manner (10⁻⁷ to 10⁻⁵ M). Thesedata demonstrated that paclitaxel was a potent inhibitor of AP-1activity in chondrocytes.

3. Effect of paclitaxel on AP-1 DNA binding activity

To confirm that paclitaxel inhibition of AP-1 activity was not due tononspecific effects, the effect of paclitaxel on IL-1 induced AP-1binding to oligonucleotides using chondrocyte nuclear lysates wasexamined. As shown in FIG. 4C, IL-1 induced binding activity decreasedin lysates from chondrocyte which had been pretreated with paclitaxel atconcentration 10⁻⁷ to 10⁻⁵ M for 24 hours. Paclitaxel inhibition of AP-1transcriptional activity closely correlated with the decrease in AP-1binding to DNA.

4. Effect of paclitaxel on collagenase and stromelysin expression

Since paclitaxel was a potent inhibitor of AP-1 activity, the effect ofpaclitaxel or IL-1 induced collagenase and stromelysin expression, twoimportant matrix metalloproteinases involved in inflammatory diseaseswas examined. Briefly, as shown in FIG. 4D, IL-1 induction increasescollagenase and stromelysin mRNA levels in chondrocytes. Pretreatment ofchondrocytes with paclitaxel for 24 hours significantly reduced thelevels of collagenase and stromelysin mRNA. At 10⁻⁵ M paclitaxel, therewas complete inhibition. The results show that paclitaxel completelyinhibited the expression of two matrix metalloproteinases atconcentrations similar to which it inhibits AP-1 activity.

5. Effect of other anti-microtubules on collagenase expression

FIGS. 5A-H demonstrate that anti-microtubule agents inhibitedcollagenase expression. Expression of collagenase was stimulated by theaddition of IL-1 which is a proinflammatory cytokine. Pre-incubation ofchondrocytes with various anti-microtubule agents, specificallyLY290181, hexylene glycol, deuterium oxide, glycine ethyl ester,ethylene glycol bis-(succinimidylsuccinate), tubercidin, AlF₃, andepothilone, all prevented IL-1-induced collagenase expression atconcentrations as low as 1×10⁻⁷ M.

C. Discussion

Paclitaxel was capable of inhibiting collagenase and stromelysinexpression in vitro at concentrations of 10⁻⁶ M. Since this inhibitionmay be explained by the inhibition of AP-1 activity, a required step inthe induction of all matrix metalloproteinases with the exception ofgelatinase B, it is expected that paclitaxel may inhibit other matrixmetalloproteinases which are AP-1 dependent. The levels of these matrixmetalloproteinases are elevated in all inflammatory diseases and play aprinciple role in matrix degradation, cellular migration andproliferation, and angiogenesis. Thus, paclitaxel inhibition ofexpression of matrix metalloproteinases such as collagenase andstromelysin will have a beneficial effect in inflammatory diseases.

In addition to paclitaxel's inhibitory effect on collagenase expression,LY290181, hexylene glycol, deuterium oxide, glycine ethyl ester, AlF₃,tubercidin epothilone, and ethylene glycol bis-(succinimidylsuccinate),all prevented IL-1-induced collagenase expression at concentrations aslow as 1×10⁻⁷ M. Thus, anti-microtubule agents are capable of inhibitingthe AP-1 pathway at varying concentrations.

Example 31 Inhibition of Angiogenesis by Paclitaxel

A. Chick Chorioallantoic Membrane (“CAM”) Assays

Fertilized, domestic chick embryos were incubated for 3 days prior toshell-less culturing. In this procedure, the egg contents were emptiedby removing the shell located around the air space. The interior shellmembrane was then severed and the opposite end of the shell wasperforated to allow the contents of the egg to gently slide out from theblunted end. The egg contents were emptied into round-bottom sterilizedglass bowls and covered with petri dish covers. These were then placedinto an incubator at 90% relative humidity and 3% CO₂ and incubated for3 days.

Paclitaxel (Sigma, St. Louis, Mich.) was mixed at concentrations of0.25, 0.5, 1, 5, 10, 30 μg per 10 ul aliquot of 0.5% aqueousmethylcellulose. Since paclitaxel is insoluble in water, glass beadswere used to produce fine particles. Ten microliter aliquots of thissolution were dried on parafilm for 1 hour forming disks 2 mm indiameter. The dried disks containing paclitaxel were then carefullyplaced at the growing edge of each CAM at day 6 of incubation. Controlswere obtained by placing paclitaxel-free methylcellulose disks on theCAMs over the same time course. After a 2 day exposure (day 8 ofincubation) the vasculature was examined with the aid of astereomicroscope. Liposyn II, a white opaque solution, was injected intothe CAM to increase the visibility of the vascular details. Thevasculature of unstained, living embryos were imaged using a Zeissstereomicroscope which was interfaced with a video camera (Dage-MTIInc., Michigan City, Ind.). These video signals were then displayed at160× magnification and captured using an image analysis system (Vidas,Kontron; Etching, Germany). Image negatives were then made on a graphicsrecorder (Model 3000; Matrix Instruments, Orangeburg, N.Y.).

The membranes of the 8 day-old shell-less embryo were flooded with 2%glutaraldehyde in 0.1 M sodium cacodylate buffer; additional fixativewas injected under the CAM. After 10 minutes in situ, the CAM wasremoved and placed into fresh fixative for 2 hours at room temperature.The tissue was then washed overnight in cacodylate buffer containing 6%sucrose. The areas of interest were postfixed in 1% osmium tetroxide for1.5 hours at 4° C. The tissues were then dehydrated in a graded seriesof ethanols, solvent exchanged with propylene oxide, and embedded inSpurr resin. Thin sections were cut with a diamond knife, placed oncopper grids, stained, and examined in a Joel 1200EX electronmicroscope. Similarly, 0.5 mm sections were cut and stained with tolueneblue for light microscopy.

At day 11 of development, chick embryos were used for the corrosioncasting technique. Mercox resin (Ted Pella, Inc., Redding, Calif.) wasinjected into the CAM vasculature using a 30-gauge hypodermic needle.The casting material consisted of 2.5 grams of Mercox CL-2B polymer and0.05 grams of catalyst (55% benzoyl peroxide) having a 5 minutepolymerization time. After injection, the plastic was allowed to sit insitu for an hour at room temperature and then overnight in an oven at65° C. The CAM was then placed in 50% aqueous solution of sodiumhydroxide to digest all organic components. The plastic casts werewashed extensively in distilled water, air-dried, coated withgold/palladium, and viewed with the s 501B scanning electron microscope.

Results of the assay were as follows. At day 6 of incubation, the embryowas centrally positioned to a radially expanding network of bloodvessels; the CAM developed adjacent to the embryo. These growing vesselslie close to the surface and are readily visible making this system anidealized model for the study of angiogenesis. Living, unstainedcapillary networks of the CAM may be imaged noninvasively with astereomicroscope.

Transverse sections through the CAM show an outer ectoderm consisting ofa double cell layer, a broader mesodermal layer containing capillarieswhich lie subjacent to the ectoderm, adventitial cells, and an inner,single endodermal cell layer. At the electron microscopic level, thetypical structural details of the CAM capillaries are demonstrated.Typically, these vessels lie in close association with the inner celllayer of ectoderm.

After 48 hours exposure to paclitaxel at concentrations of 0.25, 0.5, 1,5, 10, or 30 μg, each CAM was examined under living conditions with astereomicroscope equipped with a video/computer interface in order toevaluate the effects on angiogenesis. This imaging setup was used at amagnification of 160× which permitted the direct visualization of bloodcells within the capillaries; thereby blood flow in areas of interestmay be easily assessed and recorded. For this study, the inhibition ofangiogenesis was defined as an area of the CAM (measuring 2-6 mm indiameter) lacking a capillary network and vascular blood flow.Throughout the experiments, avascular zones were assessed on a 4 pointavascular gradient (Table 1). This scale represents the degree ofoverall inhibition with maximal inhibition represented as a 3 on theavascular gradient scale. Paclitaxel was very consistent and induced amaximal avascular zone (6 mm in diameter or a 3 on the avasculargradient scale) within 48 hours depending on its concentration.

TABLE 1 Avascular Gradient 0  normal vascularity 1  lacking somemicrovascular movement 2* small avascular zone approximately 2 mm indiameter 3* avascularity extending beyond the disk (6 mm in diameter)

The dose-dependent, experimental data of the effects of paclitaxel atdifferent concentrations are shown in Table 2.

TABLE 2 Agent Delivery Vehicle Concentration Inhibition/n paclitaxelmethylcellulose (10 ul) 0.25 ug 2/11 methylcellulose (10 ul) 0.5 ug 6/11methylcellulose (10 ul) 1 ug 6/15 methylcellulose (10 ul) 5 ug 20/27 methylcellulose (10 ul) 10 ug 16/21  methylcellulose (10 ul) 30 ug31/31 

Typical paclitaxel-treated CAMs are also shown with the transparentmethylcellulose disk centrally positioned over the avascular zonemeasuring 6 mm in diameter. At a slightly higher magnification, theperiphery of such avascular zones is clearly evident; the surroundingfunctional vessels were often redirected away from the source ofpaclitaxel. Such angular redirecting of blood flow was never observedunder normal conditions. Another feature of the effects of paclitaxelwas the formation of blood islands within the avascular zonerepresenting the aggregation of blood cells.

In summary, this study demonstrated that 48 hours after paclitaxelapplication to the CAM, angiogenesis was inhibited. The blood vesselinhibition formed an avascular zone which was represented by threetransitional phases of paclitaxel's effect. The central, most affectedarea of the avascular zone contained disrupted capillaries withextravasated red blood cells; this indicated that intercellularjunctions between endothelial cells were absent. The cells of theendoderm and ectoderm maintained their intercellular junctions andtherefore these germ layers remained intact; however, they were slightlythickened. As the normal vascular area was approached, the blood vesselsretained their junctional complexes and therefore also remained intact.At the periphery of the paclitaxel-treated zone, further blood vesselgrowth was inhibited which was evident by the typical redirecting or“elbowing” effect of the blood vessels.

Example 32 Screening Assay for Assessing the Effect of Paclitaxel onSmooth Muscle Cell Migration

Primary human smooth muscle cells were starved of serum in smooth musclecell basal media containing insulin and human basic fibroblast growthfactor (bFGF) for 16 hours prior to the assay. For the migration assay,cells were trypsinized to remove cells from flasks, washed withmigration media and diluted to a concentration of 2-2.5×10 ⁵ cells/mL inmigration media. Migration media consists of phenol red free Dulbecco'sModified Eagle Medium (DMEM) containing 0.35% human serum albumin. A 100μL volume of smooth muscle cells (approximately 20,000-25,000 cells) wasadded to the top of a Boyden chamber assembly (Chemicon QCM CHEMOTAXIS96-well migration plate). To the bottom wells, the chemotactic agent,recombinant human platelet derived growth factor (rhPDGF-BB) was addedat a concentration of 10 ng/mL in a total volume of 150 μL. Paclitaxelwas prepared in DMSO at a concentration of 10⁻² M and serially diluted10-fold to give a range of stock concentrations (10⁻⁸ M to 10⁻² M).Paclitaxel was added to cells by directly adding paclitaxel DMSO stocksolutions, prepared earlier, at a 1/1000 dilution, to the cells in thetop chamber. Plates were incubated for 4 hours to allow cell migration.

At the end of the 4 hour period, cells in the top chamber were discardedand the smooth muscle cells attached to the underside of the filter weredetached for 30 minutes at 37° C. in Cell Detachment Solution(Chemicon). Dislodged cells were lysed in lysis buffer containing theDNA binding CYQUANT GR dye and incubated at room temperature for 15minutes. Fluorescence was read in a fluorescence microplate reader at˜480 nm excitation wavelength and ˜520 nm emission maxima. Relativefluorescence units from triplicate wells were averaged after subtractingbackground fluorescence (control chamber without chemoattractant) andaverage number of cells migrating was obtained from a standard curve ofsmooth muscle cells serially diluted from 25,000 cells/well down to 98cells/well. Inhibitory concentration of 50% (IC₅₀) was determined bycomparing the average number of cells migrating in the presence ofpaclitaxel to the positive control (smooth muscle cell chemotaxis inresponse to rhPDGF-BB). See FIG. 6 (IC₅₀=0.76 nM). References:Biotechniques (2000) 29: 81; J. Immunol Methods (2001) 254: 85

Example 33 Preparation of Release Buffer

The release buffer is prepared by adding 8.22 g sodium chloride, 0.32 gsodium phosphate monobasic (monohydrate) and 2.60 g sodium phosphatedibasic (anhydrous) to a beaker. 1L HPLC grade water is added and thesolution is stirred until all the salts are dissolved. If required, thepH of the solution is adjusted to pH 7.4±0.2 using either 0.1 N NaOH or0.1 N phosphoric acid.

Example 34 Release Study to Determine Release Profile of the TherapeuticAgent From a Coated Device

A sample of the therapeutic agent-loaded catheter is placed in a 15 mlculture tube. 15 ml release buffer (Example 33) is added to the culturetube. The tube is sealed with a TEFLON lined screw cap and is placed ona rotating wheel in a 37° C. oven. At various time points, the buffer iswithdrawn from the culture tube and is replaced with fresh buffer. Thewithdrawn buffer is then analyzed for the amount of therapeutic agentcontained in this buffer solution using HPLC.

Example 35 Screening Assay for Assessing the Effect of Paclitaxel onCell Proliferation

Smooth muscle cells at 70-90% confluency were trypsinized, replated at600 cells/well in media in 96-well plates and allowed to attachmentovernight. Paclitaxel was prepared in DMSO at a concentration of 10⁻² Mand diluted 10-fold to give a range of stock concentrations (10⁻⁸ M to10⁻² M). Drug dilutions were diluted 1/1000 in media and added to cellsto give a total volume of 200 μL/well. Each drug concentration wastested in triplicate wells. Plates containing cells and paclitaxel wereincubated at 37° C. for 72 hours.

To terminate the assay, the media was removed by gentle aspiration. A1/400 dilution of CYQUANT 400X GR dye indicator (Molecular Probes;Eugene, Oreg.) was added to 1X Cell Lysis buffer, and 200 μL of themixture was added to the wells of the plate. Plates were incubated atroom temperature, protected from light for 3-5 minutes. Fluorescence wasread in a fluorescence microplate reader at ˜480 nm excitationwavelength and ˜520 nm emission maxima. Inhibitory concentration of 50%(IC₅₀) was determined by taking the average of triplicate wells andcomparing average relative fluorescence units to the DMSO control. Anaverage of n=3 replicate experiments was used to determine IC₅₀ values.See FIG. 7 (IC₅₀=7 nM).

This assay also may be used assess the effect of compounds onproliferation of fibroblasts and murine macrophage cell line RAW 264.7.The results of the assay for assessing the effect of paclitaxel onproliferation of murine RAW 264.7 macrophage cell line were shown inFIG. 9 (IC₅₀=134 nM).

Reference: In vitro toxicol. (1990) 3: 219; Biotech. Histochem. (1993)68: 29; Anal. Biochem. (1993) 213: 426.

Example 36 Perivascular Administration of Paclitaxel

WISTAR rats weighing 250-300 g are anesthetized by the intramuscularinjection of lnnovar (0.33 ml/kg). Once sedated, they are then placedunder Halothane anesthesia. After general anesthesia is established, furover the neck region is shaved, the skin clamped and swabbed withbetadine. A vertical incision is made over the left carotid artery andthe external carotid artery exposed. Two ligatures are placed around theexternal carotid artery and a transverse arteriotomy is made. A number 2FRENCH FOGART balloon catheter is then introduced into the carotidartery and passed into the left common carotid artery and the balloon isinflated with saline. The catheter is passed up and down the carotidartery three times. The catheter is then removed and the ligature istied off on the left external carotid artery.

Paclitaxel (33%) in ethelyne vinyl acetate (EVA) is then injected in acircumferential fashion around the common carotid artery in ten rats.EVA alone is injected around the common carotid artery in ten additionalrats. (The paclitaxel may also be coated onto an EVA film which is thenplaced in a circumferential fashion around the common carotid artery.)Five rats from each group are sacrificed at 14 days and the final fiveat 28 days. The rats are observed for weight loss or other signs ofsystemic illness. After 14 or 28 days the animals are anesthetized andthe left carotid artery is exposed in the manner of the initialexperiment. The carotid artery is isolated, fixed at 10% bufferedformaldehyde and examined for histology.

A statistically significant reduction in the degree of initimalhyperplasia, as measured by standard morphometric analysis, indicates adrug induced reduction in fibrotic response.

1. A device, comprising a stent and a paclitaxel derivative or acomposition comprising a paclitaxel derivative, wherein the paclitaxelderivative inhibits scarring between the device and a host into whichthe device is implanted.
 2. The device of claim 1 wherein the paclitaxelderivative is 9-deoxotaxol, 7-deoxy-9-deoxotaxol,10-desacetoxy-7-deoxy-9-deoxotaxol, 9-dihydrotaxol compound,2′-O-ethoxyethyl-7-O-trietylsilyl-9-dihydrotaxol,2′-O-ethoxyethyl-9-dihydrotaxol, 10-deacetyl-9-dihydrotaxol,9-dihydrotaxol-7,9-isopropylidene ketal, 9-dihydrotaxol-7,9-propylideneacetal, or 9-dihydrotaxol-7,9-benzylidene acetal.
 3. The device of claim1 wherein the paclitaxel derivative is9-dihydrotaxol-7,9-(3,4-dihydroxy) butylidene acetal,9-dihydrotaxol-7,9-thionocarbonate, 9-dihydrotaxol-7-O-allyl ether,9-dihydrotaxol 7-O-(2,3-dihydroxypropyl) ether, 9-dihydrotaxol7-O-(2-dimethylaminoethyl) ether, 9-dihydrotaxol 7-O-(2-hydroxyethyl)ether, 9-dihydrotaxol 7-O-(2-acetoxyethyl) ether,N-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol,10-deacetyl-N-debenzoyl-N-t-butoxycarbonyl-9-dihydrotaxol, orN-debenzoyl-N-t-butylacetyl-9-dihydrotaxol.
 4. The device of claim 1wherein the paclitaxel derivative isN-debenzoyl-N-isobutoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-adamantoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-isopropoxycarbonyl-9-dihydrotaxol,N-debenzoyl-N-benzyloxycarbonyl-9-dihydrotaxol,N-debenzoyl-9-dihydrotaxol, N-debenzoyl-N-pivaloyl-9-dihydrotaxol,N-debenzoyl-N-acetyl-9-dihydrotaxol,N-debenzoyl-N-t-butylcarbamyl-9-dihydrotaxol,9-dihydro-13-acetylbaccatin III, or2′-O-(1-ethyoxyethyl)-9-dihydrotaxol.
 5. The device of claim 1 whereinthe paclitaxel derivative is4,9,12-tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,-14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,β-tertbutyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester,4,9,12(tris(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,or4,9,12-tris(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete.6. The device of claim 1 wherein the paclitaxel derivative is4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-1-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate,4,9,12-tris(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylphosphate,4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,or4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete.7. The device of claim 1 wherein the paclitaxel derivative is4,9,12-tris(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-1-undecahydro-7,14,14,17-tetramethyl-8-methylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,or4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-ethylamino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete.8. The device of claim 1 wherein the paclitaxel derivative is4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylsulfate,4,9-bis(acetyloxy)-2-benzoyloxy-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete-8-methylphosphate,4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolan-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,12-dihydroxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxete,or β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.
 9. The device of claim 1 wherein the paclitaxel derivative isβ-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cycionona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, 1,3-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methyihydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, or β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.
 10. The device of claim 1 wherein the paclitaxel derivative isβ-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(tetrahydro-oxazole-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yi)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-formyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyioxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-methoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyioxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-ethoxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-8-acetyloxymethyl-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxyl-2-benzoyloxy-8-dimethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, or β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-diethylaminomethyl-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.
 11. The device of claim 1 wherein the paclitaxel derivative isβ-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylaminomethyl-1,10-methano-20H-cyclonona[-2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylimino-1,10-methano-20H-cyclonona[2,3]benz[1,2b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methoxyimino-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-8-methylhydrazinomethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-terttert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-cyano-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dioxolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-butyloxycarbonylamino-α-hydroxybenzenepropanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-8-(1,3-dithiolane-2-yl)-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-7,14,14,17otetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(1-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, or β-benzoylamino-α-hydroxy-γ-(2-naphthyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.
 12. The device of claim 1 wherein the paclitaxel derivative isβ-benzoylamino-α-hydroxy-γ-(pyridyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-tert-benzoylamino-α-hydroxy-γ-(thienyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(furyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxyo-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(oxazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(imidazolyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, β-benzoylamino-α-hydroxy-γ-(pyrazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester, or β-benzoylamino-α-hydroxy-γ-(pyridazinyl)propanoic acid4,9-bis(acetyloxy)-2-benzoyloxy-1,2,3,4,5,6,7,8,10,13,14-undecahydro-1-hydroxy-8-hydroxymethyl-7,14,14,17-tetramethyl-1,10-methano-20H-cyclonona[2,3]benz[1,2-b]oxet-12-ylester.
 13. The device of claim 1 wherein the device delivers thepaclitaxel derivative locally to tissue proximate to the device.
 14. Thedevice of claim 1, further comprising a coating, wherein the coatingcomprises the paclitaxel derivative.
 15. The device of claim 1, furthercomprising a coating, wherein the paclitaxel derivative is present inthe coating in an amount ranging between about 0.0001% to about 1% byweight.
 16. The device of claim 1, further comprising a coating, whereinthe coating further comprises a polymer.
 17. The device of claim 1,further comprising a polymer or a polymeric carrier.
 18. The device ofclaim 1, further comprising a second pharmaceutically active agent. 19.The device of claim 18, wherein the second pharmaceutically active agentis an anti-inflammatory agent, an agent that inhibits infection, or ananti-thrombotic agent.
 20. The device of claim 1, further comprising avisualization agent or an echogenic material.
 21. The device of claim 1wherein the device is sterile.
 22. The device of claim 1 wherein thepaclitaxel derivative is released into tissue in the vicinity of thedevice after deployment of the device.
 23. The device of claim 1 whereinthe paclitaxel derivative is released in effective concentrations fromthe device over a period ranging from about 1 month to 6 months.
 24. Thedevice of claim 1 wherein the device comprises about 0.01 μg to about 10μg, about 10 μg to about 10 mg, about 10 mg to about 250 mg, about 250mg to about 1000 mg, or about 1000 mg to about 2500 mg of the paclitaxelderivative.
 25. The device of claim 1 wherein a surface of the devicecomprises less than 0.01 μg, about 0.01 μg to about 1 μg, about 1 μg toabout 10 μg, about 10 μg to about 250 μg, about 250 μg to about 1000 μg,or about 1000 μg to about 2500 μg of the paclitaxel derivative per mm²of device surface to which the paclitaxel derivative is applied.
 26. Thedevice of claim 1 wherein the stent is a vascular stent, a coronarystent, a peripheral stent, a covered stent, a gastrointestinal stent, anesophageal stent, a biliary stent, a colonic stent, a tracheal orbronchial stent, a genital-urinary stent, a nasal or sinus stent, or anENT stent.